Carbamate derivatives, process for producing the same and use thereof

ABSTRACT

Novel carbamate derivatives which are useful as drugs because of inhibiting activated blood coagulation factor X and thus exerting an anticoagulant effect. Compounds represented by the formula:  
                 
 
     wherein R 1  represents a group represented by the formula:  
                 
 
     (wherein Y 1  represents CH═CH, etc.), which may be substituted, etc.; the ring A represents an oxo-substituted nitrogen-containing heterocyclic ring which may be further substituted; R 2  represents a hydrogen atom, optionally substituted C 1-4  alkyl, etc.; R 3  represents optionally substituted C 1-4  alkyl, etc.; and Z represents an optionally substituted nitrogen containing heterocyclic group, etc., or salts thereof.

TECHNICAL FIELD

[0001] The present invention relates to a novel carbamate derivativehaving the anticoagulant activity which inhibits activated bloodcoagulation factor X (FXa) and is useful as a medicament, a process forpreparing the same and use thereof.

BACKGROUND ART

[0002] It is important to inhibit the formation of a thrombus inpreventing and/or treating cardiac infarction, cerebral thrombosis andthe like, and various anti-thombotic agents such as anti-thrombin agentsand platelet aggregation inhibitors have been developed. Nevertheless,platelet aggregation inhibitors as well as anti-thrombin agents havehemorrhagic side effects and problems in their safety, since theseagents possess a platelet aggregation-inhibiting activity in combinationwith anti-coagulative effect. On the other hand, FXa inhibitorsspecifically inhibit a coagulation factor, and thus are considered to beuseful as anticoagulant.

[0003] So far, compounds having FXa-inhibiting effects are disclosed forexample in JP 7-112970 A, JP 5-208946 A, WO-96/16940, WO96/40679, WO96/10022, WO 98/28269, WO 99/37304, WO 99/127, and the like.

[0004] Currently, there is a demand for a compound which has a strongerFXa inhibiting activity than that of the above-mentioned compoundshaving FXa inhibiting activity by oral administration, and ispractically excellent as a medicament.

SUMMARY OF THE INVENTION

[0005] The present invention provides a novel carbamate derivative whichhas the inhibiting activity specific for FXa, is effective by oraladministration, and is useful as a medicament for preventing and/ortreating diseases attributable to thrombus or infarction.

[0006] The present inventors extensively studied and, as a result, firstsynthesized a compound represented by the formula:

[0007] wherein R¹ denotes a group represented by the formula:

[0008] (wherein Y¹ denotes O, NH, S, CH₂CH₂, CH═CH, N═CH, OCH₂, SCH₂ ortwo hydrogen atoms), or a group represented by the formula:

[0009] (wherein Y² denotes O, S, N═CH or CH═CH), each of which may besubstituted,

[0010] ring A denotes a nitrogen-containing heterocyclic ring which issubstituted with an oxo group and may be further substituted, R² denotesa hydrogen atom, an optionally substituted C₁₋₄ alkyl group, anoptionally esterified carboxyl group or a cyano group, R³ denotes a C₁₋₄alkyl group or a C₂₋₄ alkenyl group, each of which may be substitutedwith a substituent selected from a halogen atom, a hydroxy group, anoptionally substituted alkoxy group, an optionally substituted aminogroup and an optionally esterified carboxyl group, and Z denotes (1) anoptionally substituted amino group, (2) an optionally substitutedhydrocarbon group, (3) an optionally substituted imidoyl group or (4) anoptionally substituted nitrogen-containing heterocyclic group, which hassuch chemical structural specificity that the compound has a carbamategroup at the 4-position of piperidine (hereinafter, referred to ascompound (I) in some cases) or a salt thereof, and found that thiscompound has an unexpectedly excellent FXa inhibiting activity based onthe specific chemical structure and can be safely administered orally asa medicament for preventing and/or treating diseases attributable tothrombus or infarction. Based on these findings, the present inventionhas been completed.

[0011] That is, the present invention relates to:

[0012] (1) Compound (I) or a salt thereof;

[0013] (2) the compound according to the above (1), wherein R¹ is anoptionally substituted naphthyl group;

[0014] (3) the compound according to the above (1), wherein R¹ is6-halogeno-2-naphthyl group;

[0015] (4) the compound according to the above(1), wherein R¹ is anoptionally substituted benzopyranyl group;

[0016] (5) the compound according to the above (1), wherein R¹ is7-halogeno-2H-3-benzopyranyl group;

[0017] (6) the compound according to the above (1), wherein R¹ is anoptionally substituted phenyl group;

[0018] (7) the compound according to the above (1), wherein R¹ is a4-C₂₋₄ alkenyl-phenyl group;

[0019] (8) the compound according to the above (1), wherein ring A is aring represented by;

[0020] wherein n denotes 1 or 2, and m denotes 2 or 3;

[0021] (9) the compound according to the above (1), wherein ring A is anoptionally substituted oxohomopiperazine ring;

[0022] (10) the compound according to the above (1), wherein ring A isan optionally substituted oxopiperazine ring;

[0023] (11) the compound according to the above (1), wherein R² is ahydrogen atom;

[0024] (12) the compound according to the above (1), wherein R³ is aC₁₋₄ alkyl group which may be substituted with a substituent selectedfrom a halogen atom, a hydroxy group, an optionally substituted alkoxygroup, an optionally substituted amino group and a optionally esterifiedcarboxyl group;

[0025] (13) the compound according to the above (1), wherein R³ ismethyl, ethyl, or propyl;

[0026] (14) the compound according to the above (1), wherein Z is anoptionally substituted imidoyl group;

[0027] (15) the compound according to the above (1), wherein Z is anoptionally substituted C₁₋₄ imidoyl group;

[0028] (16) the compound according to the above (1), wherein Z is anoptionally substituted amidino group;

[0029] (17) the compound according to the above (1), wherein Z is anoptionally substituted nitrogen-containing heterocyclic group;

[0030] (18) the compound according to the above (1), wherein Z is anitrogen-containing heterocyclic group which may be substituted with asubstituent selected from a C₁₋₄ alkyl group and an optionallysubstituted amino group;

[0031] (19) the compound according to the above (1), wherein Z is anoptionally substituted pyrimidyl group;

[0032] (20) the compound according to the above (1), wherein Z is anoptionally substituted pyridyl group;

[0033] (21) the compound according to the above (1), which is a compoundselected form the group consisting of4-(6-chloronaphthalene-2-sulfonyl)-1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,4-(6-chloronaphthalene-2-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-propoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-bromobenzenesulfonyl)-2-piperazinoneand1-[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)piperidin-4-ylmethyl]-4-(4-bromobenzenesulfonyl)-2-piperazinoneor a salt thereof;

[0034] (22) a prodrug of compound (I) or a salt thereof;

[0035] (23) a pharmaceutical composition, which comprises compound (I)or a salt thereof, or a prodrug thereof;

[0036] (24) the composition according to the above (23), which is ananticoagulant;

[0037] (25) the composition according to the above (23), which is anactivated blood coagulation factor X inhibiting agent;

[0038] (26) the composition according to the above (23), which is anagent for preventing and/or treating cardiac infarction, cerebralthrombosis, deep vein thrombosis, pulmonary thrombotic embolus orthrombotic embolus during or after operation;

[0039] (27) a process for preparing a compound represented by theformula:

[0040] wherein each symbol is as defined hereinafter, or a salt thereof,which comprises (i) reacting a compound represented by the formula:

R¹SO₂Q

[0041] wherein Q denotes a leaving group, and the other symbol is asdefined in the above (1), or a salt thereof, with a compound representedby the formula:

[0042] wherein the symbols are as defined in the above (1), or a saltthereof,

[0043] (ii) reacting a compound represented by the formula:

[0044] wherein the symbols are as defined in the above (1), or a saltthereof, with a compound represented by the formula:

L¹-Z

[0045] wherein L¹ denotes a leaving group, and the other symbol is asdefined in the above (1), or a salt thereof,

[0046] (iii) reacting a compound represented by the formula;

[0047] wherein the symbols are as defined in the above (1), or a saltthereof, with a compound represented by the formula:

L²-COOR³

[0048] wherein L² denotes a leaving group, and the other symbol is asdefined in the above (1), or a salt thereof;

[0049] (28) a method for inhibiting blood coagulation in a mammal, whichcomprises administering an effective amount of the compound according tothe above (1) or a salt thereof, or a prodrug thereof to the mammal;

[0050] (29) a method for inhibiting activated blood coagulation factor Xin a mammal, which comprises administering an effective amount of thecompound according to the above (1) or a salt thereof, or a prodrugthereof to the mammal;

[0051] (30) a method for preventing and/or treating cardiac infarction,cerebral thrombosis, deep vein thrombosis, pulmonary thrombotic embolusor thrombotic embolus during or after operation in a mammal, whichcomprises administering an effective amount of the compound according tothe above (1) or a salt thereof, or a prodrug thereof to the mammal;

[0052] (31) use of the compound according to the above (1) or a saltthereof, or a prodrug thereof for manufacturing a medicament forinhibiting blood coagulation;

[0053] (32) use of the compound according to the above (1) or a saltthereof, or a prodrug thereof for manufacturing a medicament forinhibiting activated blood coagulation factor X;

[0054] (33) use of the compound according to the above (1) or a saltthereof, or a prodrug thereof for preparation of a medicament forpreventing and/or treating cardiac infarction, cerebral thrombosis, deepvein thrombosis, pulmonary thrombotic embolus or thrombotic embolusduring or after operation.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

[0055] In the above mentioned formulas, R¹ denotes a group representedby the formula:

[0056] wherein Y¹ denotes O, NH, S, CH₂CH₂, CH═CH, N═CH, OCH₂, SCH₂ ortwo hydrogen atoms, or a group represented by the formula:

[0057] wherein Y² denotes O, S, N═CH or CH═CH, each of which may besubstituted.

[0058] Examples of the above group represented by the formula:

[0059] wherein Y¹ denotes O, NH, S, CH₂CH₂, CH═CH, N═CH, OCH₂, SCH₂ ortwo hydrogen atoms and, in case that two kinds of atoms are present inatoms constituting a straight chain part of Y¹, any of left and rightatoms may be bound to a carbon atom having a bond to SO₂ and, forexample, when Y¹ is N═CH, it may be either N═CH—[carbon atom having abond to SO₂] or CH═N—[carbon atom having a bond to SO₂], includeβ-styryl group, 2-naphthyl group, 3-dihydronaphthyl group, 3-quinolylgroup, 3-isoquinolyl group, 2H-3-benzopyranyl group,2H-3-benzothiopyranyl group, 2-benzothienyl group, 2-benzofuranyl group,2-indolyl group, and the like.

[0060] In addition, when Y¹ denotes two hydrogen atoms, the “grouprepresented by the formula:

[0061] wherein Y¹ denotes two hydrogen atoms, which may be substituted”as R¹ means an “group represented by the formula:

[0062] which may be substituted”.

[0063] Examples of the above group represented by the formula:

[0064] wherein Y² denotes O, S, N═CH, or CH═CH and, in case that twokinds of atoms are present in atoms constituting a straight chain partof Y², any of left and right atoms may be bound to a carbon atom havinga bond to SO₂ and, for example, when Y² is N═CH, it may be eitherN═CH—[carbon atom having a bond to SO₂] or CH═N—[carbon atom having abond to SO₂], include phenyl group, 2-furyl group, 2-thienyl group,2-pyridyl group, 3-pyridyl group, and the like.

[0065] Examples of the substituent which may be possessed by the grouprepresented by R¹ include an optionally substituted alkyl group, anoptionally substituted alkenyl group, and optionally substituted alkynylgroup, an optionally substituted aryl group, an optionally substitutedcycloalkyl group, an optionally substituted cycloalkenyl group, anoptionally substituted heterocyclic group, an optionally substitutedamino group, an optionally substituted imidoyl group (e.g. a grouprepresented by the formula: —C(U′)═N-U [wherein U and U′ each denotes ahydrogen atom or a substituent (U preferably denotes a hydrogen atom)]etc.), an optionally substituted amidino group (e.g. a group representedby the formula: —C(NT′T″)═N-T [wherein T, T′ and T″ each denotes ahydrogen atom or a substituent (T preferably denotes a hydrogen atom)]etc.), an optionally substituted hydroxy group (preferably, optionallysubstituted C₁₋₄ alkoxy group such as methoxy, ethoxy, n-propoxy groupand the like, each of which may be substituted), an optionallysubstituted thiol group, an optionally esterified carboxyl group, anoptionally substituted carbamoyl group, an optionally substitutedthiocarbamoyl group, an optionally substituted sulfamoyl group, ahalogen atom (e.g. fluorine, chlorine, bromine, iodine etc, preferablychlorine, bromine, etc), a cyano group, a nitro group, a sulfonicacid-derived acyl group, a carboxylic acid-derived acyl group(preferably, halogen, an optionally substituted C₁₋₄ alkyl group, anoptionally substituted C₂₋₄ alkenyl group, an optionally substitutedaryl group, an optionally substituted 5- to 6-membered aromaticheterocyclic group, an optionally substituted C₁₋₄ alkoxy group, anoptionally substituted amino group, an optionally esterified carboxylgroup, a cyano group, an amidino group, etc.), and the like. Theseoptional substituents may occur 1 to 5 (preferably 1 to 3; morepreferably 1 to 2) times at any possible positions. In addition, a grouprepresented by R¹ may have an oxo group and, for example, when R¹ isbenzopyranyl, R¹ may form benzo-α-pyronyl, benzo-γ-pyronyl, or the like.

[0066] Examples of the aryl group in the “optionally substituted arylgroup” as the substituent include C₆₋₁₄ aryl groups such as phenyl,naphthyl, anthryl, phenanthryl, acenaphthylenyl, and the like. Examplesof the substituent for the aryl group include a lower alkoxy group (e.g.C₁₋₆ alkoxy group such as methoxy, ethoxy, propoxy, etc.), a halogenatom (e.g. fluorine, chlorine, bromine, iodine, etc.), a lower alkylgroup (e.g. C₁₋₆alkyl group such as methyl, ethyl, propyl, etc.), alower alkenyl group (e.g. C₂₋₆ alkenyl group such as vinyl, allyl,etc.), a lower alkynyl group (e.g. C₂₋₆ alkynyl group such as ethynyl,propargyl, etc.), an optionally substituted amino group, an optionallysubstituted hydroxy group, a cyano group, a C₁₋₄ alkylsulfonyl group, asulfamoyl group, an optionally substituted amidino group, and the like.These optional substituents may occur 1 to 3 times at any possiblepositions.

[0067] Examples of the “optionally substituted amino group”, the“optionally substituted hydroxy group” and the “optionally substitutedamidino group” as the substituent include the same “optionallysubstituted amino group”, “optionally substituted hydroxy group” and“optionally substituted amidino group” as those of the substituent whichmay be possessed by a group represented by R¹.

[0068] Examples of the cycloalkyl group in the “optionally substitutedcycloalkyl group” as the substituent include C₃₋₇ cycloalkyl groups suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andthe like. Here, examples of the substituent for the cycloalkyl groupinclude the same number of the same substituents as those in theabove-mentioned “optionally substituted aryl group”.

[0069] Examples of the cycloalkenyl group in the “optionally substitutedcycloalkenyl group” as the substituent include C₃₋₆ cycloalkenyl groupssuch as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, andthe like. Here, examples of the substituent for the optionallysubstituted cycloalkenyl group include the same number of the samesubstituents as those in the above-mentioned “optionally substitutedaryl group”.

[0070] Examples of the alkyl group in the “optionally substituted alkylgroup” as the substituent include C₁₋₆ alkyl groups such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,3,3-dimethylpropyl, and the like (preferably, C₁₋₄ alkyl groups such asmethyl, ethyl, n-propyl, n-butyl, etc.). Here, examples of thesubstituent for the alkyl group include the same number of the samesubstituents as those in the above-mentioned “optionally substitutedaryl group”.

[0071] Examples of the alkenyl group in the “optionally substitutedalkenyl group” as the substituent include C₂₋₆ alkenyl groups such asvinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl, and the like (preferably, C₂₋₄ alkenylgroups such as vinyl, allyl, propenyl, 1-butenyl, etc.; more preferably,vinyl). Here, examples of the substituent for the alkenyl group includethe same number of the same substituents as those in the above-mentioned“optionally substituted aryl group”.

[0072] Examples of the alkynyl group in the “optionally substitutedalkynyl group” as the substituent include C₂₋₆ alkynyl groups such asethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl, and the like (preferably, C₂₋₄ alkynylgroups). Here, examples of the substituent for the alkynyl group includethe same number of the same substituents as those in the above-mentioned“optionally substituted aryl”.

[0073] Examples of the heterocyclic group in the “optionally substitutedheterocyclic group” as the substituent include an aromatic heterocyclicgroup, a saturated or unsaturated non-aromatic heterocyclic group(aliphatic heterocyclic group), and the like, which contains at leastone (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 kinds(preferably 1 to 2 kinds) of hetero atoms selected from an oxygen atom,a sulfur atom and a nitrogen atom as an atom (ring atom) constituting aring system.

[0074] Examples of the “aromatic heterocyclic group” include a 5- to6-membered aromatic monocyclic heterocyclic group such as aromaticmonocyclic heterocyclic group (e.g. furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, etc.; preferably pyridyl, thienyl,furyl, etc.) and 8- to 16-membered (preferably 8- to 12-membered)aromatic fused heterocyclic group such as aromatic fused heterocyclicgroup (e.g. benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl,isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl,1,2-benzoisoxazoly, benzothiazolyl, 1,2-benzoisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathynyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, etc.) (preferably a heterocyclic ringin which the above-mentioned one to two (preferably one) 5- to6-membered aromatic monocyclic heterocyclic group(s) is (are) fused withone to two (preferably one) benzene ring(s) or a heterocyclic ring inwhich the above-mentioned two to three (preferably two) same ordifferent 5- to 6-membeed aromatic monocyclic heterocyclic groups arefused).

[0075] Examples of the “non-aromatic heterocyclic group” include 3- to8-membered (preferably 5- to 6-membered) saturated or unsaturated(preferably saturated) non-aromatic heterocyclic group (aliphaticheterocyclic group) such as oxiranyl, azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl, piperazinyl, and the like, andnon-aromatic heterocyclic group in which a part or all of double bondsof the above-mentioned aromatic monocyclic heterocyclic group oraromatic fused heterocyclic group are saturated, such as1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, and the like.

[0076] Examples of the substituent which may be possessed by the“optionally substituted heterocyclic group” as the substituent include alower alkyl group (e.g. C₁₋₆ alkyl groups such as methyl, ethyl, propyl,etc.), a lower alkenyl group (C₂₋₆ alkenyl groups such as vinyl, allyl,etc.), a lower alkynyl group (e.g. C₂₋₆ alkynyl groups such as ethynyl,propargyl, etc.), an acyl group (e.g. C₁₋₆ alkanoyl (e.g. formyl,acetyl, propionyl, pivaloyl, etc.), C₁₋₆ alkylsulfonyl (e.g.methanesulfonyl, ethanesulfonyl etc.), benzoyl, benzenesulfonyl, etc.),an optionally substituted amino group, an optionally substituted hydroxygroup, a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.,preferably chlorine, bromine, etc.), an optionally substituted imidolylgroup, an optionally substituted amidino group, and the like.

[0077] Examples of the “optionally substituted amino group”, the“optionally substituted hydroxy group”, the “optionally substitutedimidoyl group” and the “optionally substituted amidino group” which maybe possesses by the “optionally substituted heterocyclic group” as thesubstituent include the same “optionally substituted hydroxy group”,“optionally substituted imidoyl group” and “optionally substitutedamidino group” as those of the substituent which may be possesses by agroup represented by R¹.

[0078] Examples of the substituent in the “optionally substituted aminogroup”, the “optionally substituted imidoyl group”, the “optionallysubstituted amidino group”, the “optionally substituted hydroxy group”and the “optionally substituted thiol group” as the substituent whichmay be possesses by a group represented by R¹ include a lower alkylgroup (e.g. C₁₋₆ alkyl groups such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group (e.g. C₁₋₆alkanoyl (e.g. formyl, acetyl, propionyl, pivaloyl, etc.), C₁₋₆alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), benzoyl,benzenesulfonyl, etc.), carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, optionally halogenated C₁₋₆ alkoxycarbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl,2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, etc.), etc.), a heterocyclic group (thesame “heterocyclic group” as that of the substituent which may bepossessed by a group represented by R¹, preferably pyridyl, morepreferably 4-pyirdyl), and the like. The “amino group” in the“optionally substituted amino group” as the substituent may besubstituted with an optionally substituted imidoyl group (e.g. C₁₋₆alkylimidoyl, C₁₋₆ alkanoylimidoyl (e.g. formylimidoyl, etc.), amidino,etc.), or an amino group optionally substituted with 1 to 2C₁₋₆alkyl(s), etc. Alternatively, two substituents may be taken togetherwith the nitrogen atom to form a cyclic amino group, and examples ofsuch the cyclic amino group include 3- to 8-membered (preferably 5- to6-membered) cyclic.amino such as 1-azetidinyl, 1-pyrrolidinyl,piperidino, thiomorpholino, morpholino, 1-piperazinyl and 1-piperazinyloptionally having at the 4-position a lower alkyl group (e.g. C₁₋₆ alkylgroups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl,hexyl, etc.), an aralkyl group (e.g. C₇₋₁₀ aralkyl groups such asbenzyl, phenethyl, etc.), an aryl group (e.g. C₆₋₁₀ aryl groups such asphenyl, 1-naphthyl, 2-naphthyl, etc.), and the like, 1-pyrrolyl,1-imidazolyl, and the like.

[0079] As the “optionally substituted amino group” as the substituent,preferred are amino, methylamino, dimethylamino, acetylamino,methanesulfoneamino, ureido, etc.

[0080] Examples of the “optionally substituted carbamoyl group” includeN-monosubstituted carbamoyl group and N,N-disubstituted carbamoyl group,in addition to unsubstituted carbamoyl.

[0081] The “N-monosubstituted carbamoyl group” means a carbamoyl grouphaving one substituent on the nitrogen atom, and examples of thesubstituent include a lower alkyl group (e.g.C₁₋₆ alkyl groups such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-pentyl, hexyl,etc.), a lower alkenyl group (e.g. C₂₋₆ alkenyl groups such as vinyl,allyl, isopropenyl, propenyl, butenyl, pentenyl, hexenyl, etc.), acycloalkyl group (e.g. C₃₋₆ cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc.), an aryl group (e.g. C₆₋₁₀aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, etc.), an aralkylgroup (e.g. C₇₋₁₀ aralkyl groups such as benzyl, phenethyl, etc.,preferably a phenyl-C₁₋₄ alkyl group, etc.), an arylalkenyl group (e.g.C₈₋₁₀ arylalkenyl groups such as cinnamyl, etc., preferably aphenyl-C₂₋₄ alkenyl group, etc.), a heterocyclic group (e.g. the same“heterocyclic group” as that of the substituent which may be possessesby a group represented by R¹), and the like. The lower alkyl group, thelower alkenyl group, the cycloalkyl group, the aryl group, the aralkylgroup, the arylalkenyl group and the heterocyclic group may havesubstituent(s), and examples of the substituent include a hydroxy group,an optionally substituted amino group [the amino group may have 1 or 2substituent(s) such as a lower alkyl group (e.g. C₁₋₆ alkyl groups suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, etc.), an acyl group (e.g. C₁₋₆ alkanoyl (e.g. formyl, acetyl,propionyl, pivaloyl, etc.), C₁₋₆ alkylsulfonyl (e.g. methanesulfonyl,ethanesulfonyl, etc.), benzoyl, benzenesulfonyl, etc.), a carboxylgroup, a C₁₋₆-alkoxy-carbonyl group, etc.], a halogen atom (e.g.fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyanogroup, a lower alkyl group optionally substituted with 1 to 5 halogenatom(s) (e.g. fluorine, chlorine, bromine, iodine, etc.), a lower alkoxygroup optionally substituted with 1 to 5 halogen atom(s) (e.g. fluorine,chlorine, bromine, iodine, etc.), and the like. Examples of the loweralkyl group include C₁₋₆ alkyl groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, andthe like and, in particular, methyl, ethyl, and the like are preferable.Examples of the lower alkoxy group include C₁₋₆ alkoxy groups such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, and the like and, in particular, methoxy, ethoxy, and thelike are preferable. In addition, these substituents may be the same ordifferent and the number of the substituent(s) is preferably 1, 2 or 3(preferably 1 or 2).

[0082] The “N,N-disubstituted carbamoyl group” means a carbamoyl groupwhich has two substituents on the nitrogen atom, and examples of one ofthe substituents include the same substituents as those in theabove-mentioned “N-monosubstituted carbamoyl group”, and examples of theother substituent include a lower alkyl group (e.g. C₁₋₆ alkyl groupssuch as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl,etc.), a C₃₋₆ cycloalkyl group (e.g. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, etc.), a C₇₋₁₀aralkyl group (e.g. benzyl,phenethyl, etc., preferably a phenyl-C₁₋₄ alkyl group etc.), and thelike. Alternatively, two substituents may be taken together with thenitrogen atom to form a cyclic amino group, and examples of the cyclicaminocarbamoyl group in such the case include 3- to 8-membered(preferably 5- to 6-membered) cyclic amino-carbamoyl such as1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl,morpholinocarbonyl, 1-piperazinylcarbonyl and 1-piperazinylcarbonyloptionally having at the 4-position a lower alkyl group (e.g. C₁₋₆ alkylgroups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl,hexyl, etc.), an aralkyl group (e.g. C₇₋₁₀ aralkyl groups such asbenzyl, phenethyl, etc.), an aryl group (e.g. C₆₋₁₀ aryl groups such asphenyl, 1-naphthyl, 2-naphtyl, etc.).

[0083] Examples of the substituent for the “optionally substitutedthiocarbamoyl group” and the “optionally substituted sulfamoyl group”include the same substituents as those for the above-mentioned“optionally substituted carbamoyl group”.

[0084] Examples of the optionally esterified carboxyl group include alower alkoxycarbonyl group, an aryloxycarbonyl group, anaralkyloxycarbonyl group, and the like, in addition to a free carboxylgroup.

[0085] Examples of the “lower alkoxycarbonyl group” include C₁₋₆alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl, and the like and, interalia, C₁₋₃ alkoxy-carbonyl groups such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, and the like are preferable.

[0086] As the “aryloxycarbonyl group”, preferred are, for example, C₇₋₁₂aryloxy-carbonyl groups such as phenoxycarbonyl, 1-naphthoxycarbonyl,2-naphthoxycarbonyl, and the like.

[0087] As the “aralkyloxycarbonyl group”, preferred are, for example,C₇₋₁₀ aralkyloxy-carbonyl groups such as benzyloxycarbonyl,phenethyloxycarbonyl, and the like (preferably, C₆₋₁₀ aryl-C₁₋₄alkoxy-carbonyl, etc.)

[0088] The “aryloxycarbonyl group”, and the “aralkyloxycarbonyl group”may have substituent(s), and, as the substituent, the same number of thesame substituents as those of the aryl group and aralkyl group describedas the substituent for the above-mentioned N-monosubstituted carbamoylgroup can be used.

[0089] Examples of the “sulfonic acid-derived acyl group” as thesubstituent include sufonyl bound to one substituent on the nitrogenatom of the above-mentioned “N-monosubstituted carbamoyl group”,preferably acyls such as C₁₋₆ alkylsulfonyl such as methanesulfonyl,ethanesulfonyl, and the like.

[0090] Examples of the “carboxylic acid-derived acyl group” as thesubstituent include carbonyl bound to a hydrogen atom or one substituenton the nitrogen atom of the above-mentioned “N-monosubstituted carbamoylgroup”, preferably acyls such as C₁₋₆ alkanoyl such as formyl, acetyl,propionyl, pivaloyl, and the like, and benzoyl, and the like.

[0091] As R¹, preferred are an optionally substituted naphthyl group, anoptionally substituted phenyl group, an optionally substitutedbenzopyranyl group, and the like and, inter alia, an aryl groupoptionally substituted with a halogen atom or C₂₋₄ alkenyl (preferablyC₆₋₁₄ aryl such as phenyl, 1-naphtyl, 2-naphthyl, etc.), a benzopyranylgroup optionally substituted with a halogen atom and, inter alia,6-halogeno-2-naphthyl group, 4-vinylpheyl group and7-halogeno-2H-3-benzopyranyl group are preferable.

[0092] In the above formulas, ring A denotes a nitrogen-containingheterocyclic ring which is substituted with an oxo group and may befurther substituted, that is, a nitrogen-containing heterocyclic ringwhich may have an optional substituent at any possible position inaddition to one oxo group expressly shown as the substituent. Theposition replaced with the oxo group may be any possible position, andit is preferable that the oxo group replaces on the carbon atom adjacentto the nitrogen atom to which a group represented by the formula—CH(R²)— is bound.

[0093] Examples of the “nitrogen-containing heterocyclic ring” in the“nitrogen-containing heterocyclic ring which is substituted with an oxogroup and may be further substituted” represented by ring A include aring in which the oxo group is bound to a replaceable position of a 6-to 8-membered nitrogen-containing heterocyclic ring containing at leasttwo nitrogen atoms in addition to carbon atoms, and optionally furthercontaining 1 to 3 hetero atom(s) selected from an oxygen atom, a sulfuratom and the like as an atom constituting the ring system (ring atom)(preferably 6- to 8-membered nitrogen-containing heterocyclic ringcomposed of carbon atoms and at least two nitrogen atoms), and the like.

[0094] It is essential that the “6- to 8-membered nitrogen-containingheterocyclic ring” has the oxo group, and examples thereof, when the oxogroup is omitted and the heterocyclic ring is exemplified as a divalentgroup, include a divalent 6-membered nitrogen-containing heterocyclicgroup containing 2 to 4 nitrogen atoms such as piperazinediyl(piperazine-1,4-diyl, etc.), tetrahydropyrazinediyl,triazacyclohexanediyl, tetraazacyclohexanediyl, tetrahydrotriazinediyland the like, a divalent 7-membered nitrogen-containing heterocyclicgroup containing 2 to 4 nitrogen atoms such as homopiperazinediyl(homopiperazine-1,4-diyl, etc), 2,3-dehydrohomopiperazinediyl and thelike, and a divalent 8-membered nitrogen-containing heterocyclic groupcontaining 2 to 4 nitrogen atoms such as 1,4-diazacyclooctanediyl(1,4-diazacyclooctane-1,4-diyl, etc), 1,5-diazacyclooctanediyl(1,5-diazacyclooctane-1,5-diyl, etc.), and the like.

[0095] These “divalent nitrogen-containing heterocyclic groups” have theoxo group at a possible replaceable position and, inter alia, it ispreferable that it is a “divalent 6- to 8-membered nitrogen-containingcyclic amido group” having the oxo group on the carbon atom adjacent tothe nitrogen atom to which a group represented by the formula —CH(R²)—is bound. Examples of the “divalent 6- to 8-membered nitrogen-containingcyclic amido group” include 2-oxopiperazin-1,4-diyl,2-oxo-1,2,3,4-tetrahydropyrazin-1,4-diyl, 2-oxohomopiperazin-1,4-diyl,5-oxohomopiperazin-1,4-diyl, 2-oxo-1,4-diazacyclooctan-1,4-diyl,5-oxo-1,4-diazacyclooctan-1,4-diyl, 2-oxo-1,5-diazacyclooctan-1,5-diyl,5-oxo-2,3-dehydrohomopiperazin-1,4-diyl,3-oxo-1,2,4-triazacyclohexan-1,4-diyl,3-oxo-1,2,3,4-tetrahydro-1,2,4-triaziyn-1,4-diyl,6-oxo-1,2,4-triazacyclohexan-1,4-diyl,3-oxo-1,2,4,5-tetraazacyclohexan-1,4-diyl, and the like.

[0096] Examples of the substituent for the “nitrogen-containingheterocyclic ring” in the “nitrogen-containing heterocyclic ring whichis substituted with an oxo group and may be further substituted”represented by ring A include, in addition to one oxo group, anoptionally substituted hydroxy group, an optionally substituted mercaptogroup, a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.),a nitro group, a cyano group, an oxo group, an optionally substitutedamino group, an optionally substituted lower alkyl group, an optionallysubstituted lower alkylidene group, an optionally substituted loweraralkylidene group, a lower alkoxy group optionally substituted with 1to 5 halogen atom(s) (e.g. fluorine, chlorine, bromine, iodine, etc.),an optionally esterified carboxyl group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, and the like, and these optionalsubstituents may occur 1 to 3 (preferably 1 to 2) times at any possibleposition(s).

[0097] Here, examples of the substituent for the “optionally substitutedamino group” include 1 to 2 optionally substituted alkyl group(s),optionally substituted carbamoyl group(s), optionally substitutedthiocarbamoyl group(s), optionally substituted sulfamoyl group(s),optionally esterified carboxyl group(s), sulfonic acid-derived acylgroup(s), carboxylic acid-derived acyl group(s) and the like. Examplesof the “optionally substituted alkyl group”, the “optionally substitutedcarbamoyl group”, the “optionally substituted thiocarbamoyl group”, the“optionally substituted sulfamoyl group”, the “optionally esterifiedcarboxyl group”, the “sulfonic acid-derived acyl group” and the“carboxylic acid-derived acyl group” include the same “optionallysubstituted alkyl group”, “optionally substituted carbamoyl group”,“optionally substituted thiocarbamoyl group”, “optionally substitutedsufamoyl group”, “optionally esterified carboxyl group”, “sulfonicacid-derived acyl group” and “carboxylic acid-derived acyl group” asthose of the substituent for a group represented by R¹, and preferredexamples of the “optionally substituted amino group” include aminooptionally having 1 to 2 substituent(s) selected from (1) lower (C₁₋₆)alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl and the like, (2) a mono-or di-lower(C₁₋₆) alkylcarbamoyl group, (3) a C₁₋₆ alkylsulfonyl such asmethanesulfonyl, ethanesufonyl, and the like, (4) a C₁₋₆ alkanoyl suchas formyl, acetyl, propionyl, pivaloyl and the like and (5) benzoyl, andthe like.

[0098] Examples of the lower alkyl group in the “optionally substitutedlower alkyl group” include a C₁₋₆ alkyl group such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and thelike and, in particular, methyl, ethyl, and the like are preferable.Examples of the substituent therefor include a halogen atom (e.g.fluorine, chlorine, bromine, iodine etc.), an amino group, a carboxylgroup, a hydroxy group, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryl-C₁₋₄alkoxy, and the like, and these optional substituents may occur 1 to 5(preferably 1 or 2) times at any possible replaceable position(s).

[0099] Examples of the “optionally substituted lower alkylidene group”include C₁₋₆ alkylidene such as methylidene, ethylidene, and the like,examples of the substituent therefor include a halogen atom (e.g.fluorine, chlorine, bromine, iodine etc.), an amino group, a carboxylgroup, a hydroxy group, and the like, and these optional substituentsmay occur 1 to 5 (preferably 1 or 2) times at any possible position(s).

[0100] Examples of the “optionally substituted lower aralkylidene group”include C₆₋₁₀ aryl-C₁₋₄ alkylidene such as benzylidene, and the like,examples of the substituent therefor include a halogen atom (e.g.fluorine, chlorine, bromine, iodine, etc.), an amino group, a carboxylgroup, a hydroxy group and the like, and these optional substituents mayoccur 1 to 5 (preferably 1 or 2) times at any possible position(s).

[0101] Examples of the lower alkoxy group in the “lower alkoxy groupoptionally substituted with a halogen atom” include C₁₋₆ alkoxy groupssuch as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, tert-butoxy, and the like and, in particular, methoxy,ethoxy, and the like are preferable.

[0102] Examples of the “optionally esterified carboxyl group” includethe same optionally esterified carboxyl groups as those of thesubstituent for the above-mentioned group represented by R¹.

[0103] Examples of the “optionally substituted carbamoyl group”, the“optionally substituted thiocarbamoyl group” and the “optionallysubstituted sulfamoyl group” include the same optionally substitutedcarbamoyl group, optionally substituted thiocarbamoyl group andoptionally substituted sulfamoyl group as those of the substituent forthe above-mentioned group represented by R¹.

[0104] In the “optionally substituted hydroxy group” and the “optionallysubstituted mercapto group” as the substituent which may be possessed bythe “nitrogen-containing heterocyclic ring which is substituted with anoxo group and may be further substituted” represented by ring A,examples of the substituent which may be possessed by the “hydroxygroup” and the “mercapto group” include an optionally substituted loweralkyl group, an optionally esterified carboxyl group, an optionallysubstituted carbamoyl group, an optionally substituted thiocarbamoylgroup, an optionally substituted sulfamoyl group, a sulfonicacid-derived acyl group, a carboxylic acid-derived acyl group, and thelike. Examples of the lower alkyl group include a C₁₋₆ alkyl group suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, and the like, and examples of the substituentwhich may be possessed by the lower alkyl group include a halogen group(e.g. fluorine, chlorine, bromine, iodine, etc.), an optionallysubstituted aryl group [for example, phenyl or naphthyl each optionallysubstituted with a halogen atom (e.g. fluorine, chlorine, bromine,iodine, etc.), a lower alkyl group (e.g. C₁₋₆ alkyl groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, etc.), a lower alkoxy group (e.g. C₁₋₆ alkoxygroups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, etc.), and the like], an optionallysubstituted hydroxy group (e.g. the same optionally substituted hydroxygroup as that of the substituent for the above-mentioned grouprepresented by R¹), an optionally substituted thiol group (e.g. the sameoptionally substituted thiol group as that of the substituent for theabove-mentioned group represented by R¹), an optionally substitutedamino group (e.g. the same optionally substituted amino group as that ofthe substituent for the above-mentioned group represented by R¹), anoptionally esterified carboxyl group (e.g. the same optionallyesterified carboxyl group as that of the substituent for theabove-mentioned group represented by R¹), and the like. Further, in the“optionally substituted mercapto group”, the sulfur atom may be oxidizedand, for example, may have a structure represented by S(O)_(k) [kdenotes an integer of 0 to 2].

[0105] In the “optionally substituted hydroxy group” and the “optionallysubstituted mercapto group” as the substituent which may be possessed bythe “nitrogen-containing heterocyclic ring which is substituted with anoxo group and may be further substituted” represented by ring A,examples of the “optionally esterified carboxyl group”, the “optionallysubstituted carbamoyl group”, the “optionally substituted thiocarbamoylgroup”, the “optionally substituted sulfamoyl group”, the “sulfonicacid-derived acyl group” and the “carboxylic acid-derived acyl group” asthe substituent which may be possessed by the “hydroxy group” and the“mercapto group” include the same “optionally esterified carboxylgroup”, “optionally substituted carbamoyl group”, “optionallysubstituted thiocarbamoyl group”, “optionally substituted sulfamoylgroup”, “sulfonic acid-derived acyl group” and “carboxylic acid-derivedacyl group” as those of the substituent for the above-mentioned grouprepresented by R¹.

[0106] As ring A, for example, a ring represented by the formula:

[0107] wherein n denotes 1 or 2, and m denotes 2 or 3, and the like arepreferable.

[0108] In the above-mentioned formula, as m, 2 is preferable and, as n,1 is preferable.

[0109] In addition, as ring A, an optionally substituted oxopiperazinering or an optionally substituted oxohomopiperazine ring is preferableand, inter alia, an optionally substituted oxopiperazine ring ispreferable. In addition, when expressed as a divalent group, inter alia,2-oxopiperazin-1,4-diyl can be preferably used.

[0110] In the above-mentioned formula, R² denotes a hydrogen atom, anoptionally substituted C₁₋₄ alkyl group, an optionally esterifiedcarboxyl group, or a cyano group.

[0111] Examples of the “C₁₋₄ alkyl group” in the “optionally substitutedC₁₋₄ alkyl group” represented by R² include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like, andexamples of the substituent which may be possessed by the “C₁₋₄ alkylgroup” include the same substituents as those for the “optionallysubstituted lower alkyl group” as the substituent for theabove-mentioned “divalent nitrogen-containing heterocyclic group whichmay be further substituted” represented by ring A.

[0112] Examples of the “optionally esterified carboxyl group”represented by R² include the same “optionally esterified carboxylgroups” as the substituent for the above-mentioned group represented byR¹.

[0113] As R², a hydrogen atom is preferably used.

[0114] In the above-mentioned formula, R³ denotes a C₁₋₄ alkyl group ora C₂₋₄ alkenyl group, each of which may be substituted with asubstituent selected from a halogen atom, a hydroxy group, an optionallysubstituted alkoxy group, an optionally substituted amino group and anoptionally esterified carboxyl group.

[0115] Examples of the “C₁₋₄ alkyl group” in the “optionally substitutedC₁₋₄ alkyl group” represented R³ include methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclobutyl, and the like.

[0116] Examples of the “C₂₋₄ alkenyl group” (preferably C₃₋₄ alkenyl”)in the “optionally substituted C₂₋₄ alkenyl group” represented by R³include allyl, 2-butenyl, 3-butenyl, and the like.

[0117] Examples of the “optionally substituted alkoxy group” as thesubstituent for the “optionally substituted C₁₋₄ alkyl group” and the“optionally substituted C₂₋₄ alkenyl group” represented by R³ include aC₁₋₆ alkoxy group (e.g. methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.) optionallysubstituted with a substituent selected from (1) a hydroxy group, (2) anoptionally substituted amino group [the amino group may have 1 or 2substituent(s) such as a lower alkyl group (e.g. C₁₋₆ alkyl group suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, etc.), an acyl group (e.g. C₁₋₆ alkanoyl (e.g. formyl, acetyl,propionyl, pivaloyl, etc.), C₁₋₆ alkylsulfonyl (e.g. methanesulfonyl,ethanesulfonyl, etc.), benzoyl, benzenesulfonyl, etc.), a carboxylgroup, a C₁₋₆-alkoxy-carbonyl group, and the like] (3) a halogen atom(e.g. fluorine, chlorine, bromine, iodine, etc.) (4) a nitro group, (5)a cyano group, (6) a lower (C₁₋₆) alkyl group optionally substitutedwith 1 to 5 halogen atom(s) (e.g. fluorine, chlorine, bromine, iodine,etc.), (7) a lower (C₁₋₆) alkoxy group optionally substituted with 1 to5 halogen atom(s) (e.g. fluorine, chlorine, bromine, iodine, etc.), andthe like.

[0118] Examples of the “optionally substituted amino group” as thesubstituent for the “optionally substituted C₁₋₄ alkyl group” and the“optionally substituted C₂₋₄ alkenyl group” represented by R³ includethe same “optionally substituted amino groups” as those of thesubstituent which may be possessed by a group represented by R¹.

[0119] Examples of the “optionally esterified carboxy group” as thesubstituent for the “optionally substituted C₁₋₄ alkyl group” and the“optionally substituted C₂₋₄ alkenyl group” represented by R³ includethe same “optionally esterified carboxyl groups” as those of thesubstituent for the above-mentioned group represented by R¹.

[0120] As R³, a C₁₋₄ alkyl group (preferably, a C₁₋₃ alkyl group), etc.,is preferable and, inter alia, methyl or ethyl is preferably used.

[0121] In the above-mentioned formulas, Z denotes (1) an optionallysubstituted amino group, (2) an optionally substituted hydrocarbongroup, (3) an optionally substituted imidoyl group or (4) an optionallysubstituted nitrogen-containing heterocyclic group.

[0122] Examples of the substituent in the “optionally substituted aminogroup” represented by Z include an “optionally substituted hydrocarbongroup” and an “optionally substituted heterocyclic group”, while twosubstituents may be taken together with the nitrogen atom to form acyclic amino group. Examples of the cyclic amino is group in such thecase include a 3- to 8-membered (preferably 5- to 6-membered) cyclicamino such as 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino,1-piperazinyl, 1-piperazinyl optionally having at the 4-position a loweralkyl group (e.g. C₁₋₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), an aralkyl group (e.g.C₇₋₁₀ aralkyl group such as benzyl, phenethyl, etc.), an aryl group(e.g. C₆₋₁₀ aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc.),and the like, and such the cyclic amino group may have the same numberof the same substituents as those of the “optionally substitutedhydrocarbon group” as the substituent in the above-mentioned “optionallysubstituted amino group” represented by Z.

[0123] Examples of the “optionally substituted hydrocarbon group” as thesubstituent in the “optionally substituted amino group” represented by Zinclude an aliphatic chain-like hydrocarbon group, an alicyclichydrocarbon group and an aryl group and, inter alia, an aryl group ispreferable.

[0124] Examples of the “aliphatic chain-like hydrocarbon group” as anexample of the hydrocarbon group include a straight or branchedaliphatic hydrocarbon group such as an alkyl group, an alkenyl group, analkynyl group, and the like.

[0125] Here examples of the alkyl group include a C₁₋₁₀ alkyl group(preferably C₁₋₆ alkyl, etc.) such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,3,3-dimethypropyl, 2-ethylbutyl, n-heptyl, 1-methyheptyl, 1-ethylhexyl,n-octyl, 1-methylheptyl, nonyl, and the like.

[0126] Examples of the alkenyl group include a C₂₋₆ alkenyl group suchas vinyl, allyl, isopropenyl, 2-methyallyl, 1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl, and the like.

[0127] Examples of the alkynyl group include a C₂₋₆ alkynyl group suchas ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl, and the like.

[0128] Examples of the “alicyclic hydrocarbon group” as an example ofthe hydrocarbon group include a saturated or unsaturated alicyclichydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, acycloalkadienyl group, and the like.

[0129] Here, examples of the “cycloalkyl group” include C₃₋₉ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, and the like.

[0130] Examples of the “cycloalkenyl group” include a C₃₋₆ cycloalkenylgroup such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, and the like.

[0131] Examples of the “cycloalkadienyl group” include a C₄₋₆cycloalkadienyl group such as 2,4-cyclopentadien-1-yl,2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, and the like.

[0132] Examples of the “aryl group” as an example of the hydrocarbongroup include monocyclic or fused polycyclic aromatic hydrocarbongroups, for example, C₆₋₁₄ aryl groups such as phenyl, naphthyl,anthryl, phenanthryl, acenaphthylenyl, and the like and, inter alia,phenyl, 1-naphthyl, 2-naphthyl, and the like are particularlypreferable.

[0133] Examples of the “optionally substituted heterocyclic group” asthe substituent in the “optionally substituted amino group” representedby Z include an aromatic heterocyclic group, a saturated or unsaturatedaromatic heterocyclic group (aliphatic heterocyclic group), and the likecontaining at least 1 (preferably 1 to 4, more preferable 1 or 2) of 1to 3 kinds (preferably 1 to 2 kinds) of hetero atoms selected from anoxygen atom, a sulfur atom, and a nitrogen atom as an atom constitutinga ring system (ring atom).

[0134] Examples of the “aromatic heterocyclic group” include a 5- to6-membered aromatic monocyclic heterocyclic group such as an aromaticmonocyclic heterocyclic group (e.g. furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, etc.) and 8- to 16-membered(preferably 8- to 12-membered) aromatic fused heterocyclic groups suchas an aromatic fused heterocyclic group (e.g. benzofuranyl,isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, lH-indazolyl,benzindazolyl, benzoxazolyl, 1,2-benzoisoxazoly, benzothiazolyl,benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthylidinyl, pyrinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathynyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.)(preferably a heterocyclic ring in which one to two (preferably one) theabove-mentioned 5- to 6-membered aromatic monocyclic heterocyclicgroup(s) is (are) fused with one to two (preferably one) benzene ring(s)or a heterocyclic ring in which two to three (preferably two) theabove-mentioned same or different 5- to 6-membered aromatic monocyclicheterocyclic groups are fused, more preferably, a heterocyclic ring inwhich the above-mentioned 5- to 6-membered aromatic monocyclicheterocyclic group is fused with a benzene ring, particularlypreferably, benzofuranyl, benzopyranyl, etc.), and the like.

[0135] Examples of the “non-aromatic heterocyclic group” include a 3- to8-membered (preferably 5- to 6-membered) saturated or unsaturated(preferably saturated) non-aromatic heterocyclic group (aliphaticheterocyclic group) such as oxiranyl, azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl, piperazinyl, and the like, and anon-aromatic heterocyclic group in which a part or all of double bondsof the above-mentioned aromatic monocyclic heterocyclic group oraromatic fused heterocyclic group are saturated, such as1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, and the like.

[0136] Examples of the substituent for the “optionally substitutedhydrocarbon group” and the “optionally substituted heterocyclic group”as the substituent in the “optionally substituted amino group”represented by Z include the same substituents as those which may bepossessed by a group represented by R¹.

[0137] In addition, when the “optionally substituted hydrocarbon group”as the substituent in the “amino group substituted with an optionallysubstituted hydrocarbon group” represented by Z contains an “optionallysubstituted imino group” at the α-position, the “optionally substitutedamino group” represented by Z forms an amino group substituted with an“optionally substituted imidoyl group” represented by Z describedhereinafter, and for example, a group represented by the formula—N(R″)—C(R′)═N—R [wherein R″ denotes a hydrogen atom or an optionallysubstituted hydrocarbon group, R denotes a hydrogen atom, an optionallysubstituted hydroxy group, an optionally substituted hydrocarbon groupor a carboxylic acid-derived acyl group, and R′ denotes a hydrogen atom,an optionally substituted hydrocarbon group, a carboxylic acid-derivedacyl group, an optionally substituted amino group, an optionallysubstituted mercapto group or an optionally substituted hydroxy group],or the like is also included in the “optionally substituted amino group”represented by Z. In addition, when R′ denotes a mercapto group or ahydroxy group and R denotes a hydrogen atom in the “optionallysubstituted imidoyl group”, the “optionally substituted imidoyl group”may denote a group represented by the formula —C(═O)—NH₂ or —C(═S)—NH₂.

[0138] Examples of the “optionally substituted hydrocarbon group”represented by R, R′ and R″ in the above-mentioned formulas include thesame “optionally substituted hydrocarbon groups” as those of thesubstituent in the above-mentioned “optionally substituted amino group”represented by Z; examples of the “carboxylic acid-derived acyl group”represented by R and R′ include the same “carboxylic acid-derived acylgroups” as those of the substituent which may be possessed by theabove-mentioned group represented by R′; examples of the “optionallysubstituted hydroxy group” represented by R′ include the same“optionally substituted hydroxy group” as that of the substituent whichmay be possessed by the above-mentioned group represented by R¹;examples of the “optionally substituted amino group” represented by R′include the same “optionally substituted amino groups” as those of thesubstituent which may be possessed by the above-mentioned grouprepresented by R¹, or an amino group optionally having 1 to 2“optionally substituted hydrocarbon group(s)” as a substituent in theabove-mentioned “optionally substituted amino group” represented by Z;and the like.

[0139] In the compound represented by the formula (I), the compoundwherein R is a carboxylic acid-derived acyl group is useful as a prodrugof the compound wherein R is a hydrogen atom.

[0140] Examples of the “carboxylic acid-derived acyl group” representedby R include the same “carboxylic acid-derived acyl groups” as that ofthe substituent which may be possessed by the above-mentioned grouprepresented by R¹, and the “carboxylic acid-derived acyl group”represented by R may be an optionally esterified carboxyl group such asa group represented by the formula-COOR′″ [wherein R′″ denotes anoptionally substituted hydrocarbon group], and the like.

[0141] Examples of the “optionally substituted hydrocarbon group”represented by R′″ include the same “optionally substituted hydrocarbongroups” as those of the substituent in the above-mentioned “optionallysubstituted amino group” represented by Z.

[0142] Preferable examples of the “hydrocarbon group” in the “optionallysubstituted hydrocarbon group” represented by R′″ include C₁₋₆ alkyl,C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, andthe like. Examples of the substituent which may be possessed by the“hydrocarbon group” include the same number of the same substituents asthose which may be possessed by the above-mentioned group represented byR¹.

[0143] Examples of the group represented by the formula —COOR′″ include,inter alia, a C₁₋₆ alkoxy-carbonyl group (e.g. methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, etc.), a C₁₋₆ alkanoyloxy-C₁₋₆alkoxy-carbonyl group (e.g. pivaloyloxymethoxycarbonyl,1-(acetoxy)ethoxycarbonyl, acetoxy-tert-butoxycarbonyl, etc.), a C₁₋₆alkoxy-carbonyloxy-C₁₋₆ alkoxy-carbonyl group (e.g.ethoxycarbonyloxymethoxycarbonyl, etc.), a 5-C₁₋₄alkyl-2-oxo-dioxolen-4-yl-C₁₋₆ alkoxy-carbonyl group (e.g.5-methyl-2-oxo-dioxolen-4-ylmethoxycarbonyl, etc.), and the like.

[0144] As the “optionally substituted amino group” represented by Z,more specifically, for example, there can be used an amino group, amono-or di-lower (C₁₋₆) alkyl amino group (e.g. methylamino, ethylamino,benzylmethylamino, dimethylamino, diethylamino, diisobutylamino,diisopropylamino, N-ethyl-t-butylamino, benzylmethylamino, etc.) whichmay be further substituted with a C₆₋₁₀ aryl group (preferably phenyl),or the like, a group represented by the formula —N(R″)—C(R′)═N—R[wherein R″ denotes a hydrogen atom or an optionally substitutedhydrocarbon group (preferably, a hydrogen atom or a lower (C₁₋₆) alkylgroup; more preferably, a hydrogen atom), R denotes a hydrogen atom, anoptionally substituted hydroxy group, an optionally substitutedhydrocarbon group or a carboxylic acid-derived acyl group (preferably, ahydrogen atom or a carboxylic acid-derived acyl group), and R′ denotes ahydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted amino group, an optionally substituted mercaptogroup or an optionally substituted hydroxy group (preferably, a hydrogenatom, a lower (C₁₋₆) alkyl group, an amino group or a mono-or di-lower(C₁₋₆) alkyl amino group)] (e.g. a guanidino group, a formimidoylaminogroup, an acetoimidoylamino group etc.), a 5- to 6-membered cyclic aminogroup (e.g. a piperidino group, etc.), and the like.

[0145] As the “optionally substituted hydrocarbon group” represented byZ, the optionally substituted hydrocarbon group as the substituent inthe above-mentioned “optionally substituted amino group” represented byZ can be applied as such. Among them, bulky alkyl groups such asisopropyl, cyclopropyl, 2-butyl, tert-butyl, 3-pentyl, and the like arepreferable.

[0146] Examples of the “optionally substituted imidoyl group”represented by Z include a group represented by the formula —C(R′)═N—R[wherein the symbols are as defined above], and the like.

[0147] Here, when R′ denotes the optionally substituted amino group(preferably amino, methylamino, ethylamino, propylamino, dimethylamino,diethylamino, hydrazino, piperidino, piperazino, morpholino,thiomorpholino, etc.), the “optionally substituted imidoyl group”represented by Z forms an optionally substituted amidino group. Specificexamples of such the optionally substituted amidino group include anamidino group which may be substituted with 1 to 2 lower (C₁₋₆) alkylgroup(s), lower (C₁₋₆) alkanoyl group(s), benzoyl group(s), or the like(e.g. amidino, N-methylamidino, N-ethylamidino, N-propylamidino,N,N′-dimethylamidino, N,N′-diethylamidino, N-methyl-N′-diethylamidino,N-formylamidino, N-acetylamidino, etc.).

[0148] In the above-mentioned formulas, preferable examples of R includehydrogen, a lower alkyl group (e.g. a C₁₋₆ alkyl group such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, etc.), an acyl group (e.g. aC₁₋₆ alkanoyl group such as formyl, acetyl, propionyl, pivaloyl, etc.;benzoyl; C₁₋₈ alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,etc.; C₇₋₁₀ aralkyloxy-carbonyl such as benzyloxycarbonyl,phenethyloxycarbonyl, etc.), a hydroxy group, and the like, andpreferable examples of R′ include hydrogen, a lower alkyl group (C₁₋₆alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,etc.), an optionally substituted amino group (e.g. an amino group whichmay be substituted with 1 to 2 the same or different lower alkylgroup(s) (e.g. a C₁₋₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, etc.) or acyl group(s) (e.g. C₁₋₆ alkanoyl(e.g. formyl, acetyl, propionyl, pivaloyl, etc.), C₁₋₆ alkanesulfonyl(e.g. methanesulfonyl, ethanesulfonyl, etc.), benzoyl, benzenesulfonyl,etc.), a hydrazino group, a 5- to 6-membered cyclic amino group (e.g.piperidino, thiomorpholino, morpholino, piperazino, etc.), etc.), ahydroxy group, a lower alkoxy group (e.g. a C₁₋₆ alkoxy group such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.).

[0149] In the above-mentioned formulas, as R, hydrogen is preferable.

[0150] In the above-mentioned formulas, as R′, hydrogen, a lower alkylgroup or an optionally substituted amino group is preferable and, interalia, a lower alkyl group or an optionally substituted amino group ispreferable and, inter alia, an optionally substituted amino group(preferably, amino optionally substituted with C₁₋₄ alkyl) ispreferable.

[0151] Examples of the “nitrogen-containing heterocyclic group” in the“optionally substituted nitrogen-containing heterocyclic group”represented by Z include an aromatic nitrogen-containing heterocyclicgroup and a saturated or unsaturated non-aromatic nitrogen-containingheterocyclic group (aliphatic heterocyclic groups) containing, as anatom constituting a ring system (ring atom), at least 1 (preferable 1 to4, more preferable 1 to 3) nitrogen atom in addition to carbon atomsand, optionally, 1 to 3 hetero atoms selected from an oxygen and asulfur atom, and the like.

[0152] Examples of the “aromatic nitrogen-containing heterocyclic group”include an aromatic monocyclic nitrogen-containing heterocyclic groupsuch as pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl (1H-imidazol-1-yl, 1H-imidazol-4-yl, etc.), pyrazolyl,1,2,3-oxathiazolyl, 1,2,4-oxathiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-triazolyl-1-yl,1,2,4-triazolyl-4-yl, etc.), tetrazolyl, pyridyl (2-, 3-or 4-pyridyl),pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, andN-oxide thereof, a 8- to 16-membered (preferably 8- to 12-membered)aromatic fused nitrogen-containing heterocyclic group such as indolyl,isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl,1,2-benzoisoxazoly, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, futarazinyl, naphthylidinyl, purinyl, pteridinyl,carbazolyl, α-carbolyl, β-carbolyl, γ-carbolyl, acridinyl, phenoxazinyl,phenothiazinyl, phenazinyl, phenathrydinyl, phenathrolinyl, indolidinyl,pyrrolo(1,2-b)pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, and the like, and N-oxide thereof(preferably a heterocyclic ring in which one to two (preferably one) theabove-mentioned 5- to 6-membered aromatic monocyclic nitrogen-containingheterocyclic group(s) is (are) fused with one to two (preferably one)benzene ring(s), or a heterocyclic ring in which two to three(preferably two) the same or different above-mentioned 5- to 6-memberedaromatic monocyclic nitrogen-containing heterocyclic groups are fused,more preferably a heterocyclic ring in which the above-mentioned 5- to6-membered aromatic monocyclic nitrogen-containing heterocyclic group isfused with a benzene ring, etc.) and, inter alia, a 5- to 6-memberedaromatic monocyclic nitrogen-containing heterocyclic group is preferableand, inter alia, imidazolyl and pyridyl are preferable.

[0153] Examples of the “non-aromatic nitrogen-containing heterocyclicgroup” include, in addition to the partially reduced “aromaticnitrogen-containing heterocyclic group” described above (e.g.imidazolinyl, tetrahydropyrimidinyl, etc.), azetidinyl, pyrrolidinyl,piperidyl (2-, 3-or 4-piperidyl), morpholinyl, thiomorpholinyl,piperazinyl (1-piperazinyl etc.), homopiperazinyl, and the like and,inter alia, a 5- to 6-membered non-aromatic monocyclicnitrogen-containing heterocyclic group is preferable.

[0154] As the substituent for the “nitrogen-containing heterocyclicgroup” represented by Z, there can be used the same substituents asthose for the “optionally substituted hydrocarbon group” as thesubstituent in the above-mentioned “optionally substituted amino group”represented by Z. In addition, the nitrogen atom constituting thenitrogen-containing heterocyclic group may be oxidized.

[0155] As Z, preferred are an optionally substituted nitrogen-containingheterocyclic group (preferably an optionally substituted aromaticnitrogen-containing heterocyclic group; more preferably, a 6-memberedaromatic nitrogen-containing heterocyclic group such as an optionallysubstituted pyridyl group or an optionally substituted pyrimidinylgroup; particularly preferable an optionally substituted pyridyl group),and the like and, inter alia, a nitrogen-containing heterocyclic groupoptionally substituted with a substituent selected from an optionallysubstituted C₁₋₄ alkyl group and an optionally substituted amino group,etc., is preferable.

[0156] In addition, as Z, an optionally substituted imidoyl group(preferably an optionally substituted C₁₋₄ imidoyl group), and anoptionally substituted amidino group can also be preferably used.

[0157] As compound (I),4-(6-chloronaphthalen-2-sulfonyl)-1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,4-(6-chloronaphthalen-2-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-ethoxycarbonylamino-1-(1-methyl-4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-propoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-bromopenzenesulfonyl)-2-piperazinone,1-[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)piperidin-4-ylmethyl]-4-(4-bromobenzenesulfonyl)-2-piperazinoneor a salt thereof is particularly preferably used.

[0158] A prodrug for compound (I) means a compound which is convertedinto compound (I) by a reaction with an enzyme or a gastric acid underin vivo physiological conditions, i.e. a compound which undergoes anenzymatic oxidation, reduction or hydrolysis to form compound (I) and acompound which is hydrolyzed by a gastric acid to form compound (I). Aprodrug for compound (I) may for example be a compound resulting fromacylation, alkylation or phosphorylation of amino group of compound (I)(for example, a compound resulting from eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation,tert-butylation of an amino group of compound (I), etc.), a compoundresulting from acylation, alkylation, phosphorylation and boration ofhydroxyl group of compound (I) (for example, a compound resulting fromacetylation, palmitoylation, propanoylation, pivaloylation,succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation of hydroxyl group of compound (I),etc.), or a compound resulting from esterification or amidation ofcarboxyl group of compound (I) (for example, a compound resulting fromethyl esterification, phenyl esterification, carboxymethylesterification, dimethylaminomethyl esterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethyl esterification, phthalidylesterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,cyclohexyloxycarbonylethyl esterification, methylamidation of carboxylgroup of compound (I), etc.), and the like. Any of these compounds canbe produced from compound (I) by a method known per se.

[0159] A prodrug for compound (I) may also be a compound which ischanged into compound (I) under physiological conditions described in“IYAKUHIN NO KAIHATSU (Pharmaceutical development)”, Vol.7, Moleculardesign, p163-198, HIROKAWA SHOTEN, 1990.

[0160] A salt of compound (I) may for example be a pharmaceuticallyacceptable salt such as an acid addition salt with acetic acid, lacticacid, succinic acid, maleic acid, tartaric acid, citric acid, gluconicacid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid,hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid,sulfamic acid, sulfuric acid, and the like, a metal salt with sodium,potassium, magnesium, calcium, and the like, an organic salt withtrimethylamine, triethylamine, pyridine, picolin, N-methylpyrrolidine,N-methylpiperidine, N-methylmorpholine, and the like.

[0161] Compound (I) or a salt thereof can be produced, for example, bythe following methods A to C. Each of compounds described in thefollowing reaction schemes may form a salt in so far as it does notinterfere with the reaction and, as such a salt, there are the samesalts as those of compound (I).

[0162] Compound (I) can be prepared by reacting a compound representedby the formula R¹SO₂Q [wherein Q denotes a leaving group, and the othersymbol is as defined above], or a salt thereof, with Compound (II)represented by the formula (II):

[0163] wherein the symbols are as defined above, or a salt thereof.

[0164] In the above formula, Q denotes a leaving group. Examples of theleaving group represented by Q include a halogen atom (e.g. fluorine,chlorine, bromine, iodine, etc.), and a group which form a reactivederivative of sulfonic acid (e.g. sulfonic anhydride, active sulfonicamide (e.g. 1,2,4-triazolide, imidazolide, etc.), quaternaryaminesulfonyl (e.g. N-methylpyrrolidinium salt, etc.), bissulfonylimide(e.g. N-phenylbissulfonylimide etc.) etc.), and the like.

[0165] This method is carried out by reacting compound (II) or a saltthereof with a reactive derivative of sulfonic acid, and examples of asalt of compound (II) include an acid addition salt with an acid whichform an acid addition salt with compound(I) as described above.

[0166] This sulfonating reaction is generally carried out in a solvent,and a solvent which dose not interfere with the reaction isappropriately selected. Examples of such solvent include alcohols suchas methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, andthe like, ethers such as dioxane, tetrahydrofuran, diethyl ether,tert-butyl methyl ether, diisopropyl ether, ethylene glycol-dimethylether, and the like, esters such as ethyl formate, ethyl acetate,n-butyl acetate, and the like, halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, trichloroethylene,1,2-dichloroethane, and the like, hydrocarbons such as n-hexane,benzene, toluene, and the like, amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, ketones suchas acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like,nitrites such as acetonitrile, propionitrile, and the like, as well asdimethyl sulfoxide, sulfolane, hexamethylphosphoramide, water and thelike. They can be used alone or as a mixed solvent.

[0167] This reaction may be carried out in the presence of a base ifnecessary and, as such the base, there can be used inorganic bases suchas lithium hydroxide, potassium hydroxide, sodium hydroxide, sodiumcarbonate, potassium carbonate, sodium bicarbonate, and the like, andtertiary amines such as triethylamine, tri(n-propyl)amine,tri(n-butyl)amine, diisopropylethylamine, cyclohexyldimethylamine,pyridine, lutidine, γ-collidine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, and thelike.

[0168] In the reaction, about 1 to about 5 moles, preferably about 1 toabout 3 moles of a reactive derivative of sulfonic acid is used per 1mole of compound (II).

[0169] The reaction temperature is about −80° C. to about 100° C.,preferably about −50° C. to about 80° C.

[0170] The reaction time varies depending on a kind of compound (II) ora reactive derivative of sulfonic acid, a kind of a solvent, a reactiontemperature, and the like, but is usually about 1 minute to about 72hours, preferably about 15 minutes to about 24 hours.

[0171] Method B

[0172] Compound (I) or a salt thereof can be prepared by reactingcompound (III) represented by the formula (III):

[0173] wherein the symbols are as defined above, or a salt thereof, witha compound represented by the formula L¹-Z [wherein the symbols are asdefined above] or a salt thereof.

[0174] In the above-mentioned formula, the leaving group represented byL¹, when Z is an optionally substituted alkyl group or anitrogen-containing heterocyclic ring, denotes a halogen atom, a grouprepresented by the formula R⁷—SO₂—O— (wherein R⁷ denotes a lower alkylgroup optionally substituted with a halogen atom or a phenyl groupoptionally having a substituent), or an atomic group being capable ofcross coupling, for example, a group bound through boron, tin,magnesium, or the like; when Z is an optionally substituted amino group,L¹ denotes a group represented by R⁶—SO₂—O— (wherein R⁶ denotes a loweralkyl group optionally substituted with a halogen atom, a phenyl groupoptionally having a substituent, a hydroxy group, and the like) orR⁷—P(O)—O— (wherein R⁷ denotes a lower alkyl group optionallysubstituted with a halogen atom or a phenyl group optionally having asubstituent); when Z is an optionally substituted amidino group orimidoyl group, L¹ denotes, for example, an optionally substituted loweralkoxy group (e.g. a C₁₋₆ alkoxy group optionally substituted with ahalogen atom, etc.), an optionally substituted lower alkylthio group(e.g. a C₁₋₆ alkylthio group optionally substituted with a halogen atom,etc.), an optionally substituted lower alkylthionium group (e.g. a C₁₋₆alkylthionium group optionally substituted with a halogen atom, etc.),or a pyrazolyl group optionally having a substituent, etc.

[0175] In the above-mentioned formula, examples of the lower alkyl grouprepresented by R⁶ and R⁷ include a C₁₋₆ alkyl group such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, etc., and, inter alia, methyl,ethyl, propyl, isopropyl, butyl, etc., are preferably. Examples of thehalogen atom include fluorine, chlorine, bromine, iodine, and the like,and these halogen atoms may occur 1 to 9 times, preferably 1 to 5 timesat any possible position(s).

[0176] In the above-mentioned formula, examples of the substituent forthe phenyl group optionally having a substituent represented by R⁶ andR⁷ include a lower alkyl group (e.g. a C₁₋₆ alkyl group such as methyl,ethyl, propyl, butyl, etc.), a lower alkoxy group (e.g. a C₁₋₆ alkoxygroup such as methoxy, ethoxy, propoxy, butoxy, etc.), a halogen atom(e.g. fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyanogroup, a carboxyl group, etc.

[0177] This reaction is usually carried out in the presence of a base.As such base, preferably, there can be used, for example, inorganicbases such as an alkali metal hydride, e.g., sodium hydride, potassiumhydride, etc., an alkali metal hydroxide, e.g., lithium hydroxide,sodium hydroxide, potassium hydroxide, etc., an alkaline earth metalhydroxide, e.g., magnesium hydroxide, calcium hydroxide, etc., an alkalimetal carbonate, e.g., sodium carbonate, potassium carbonate, etc., analkali metal bicarbonate, e.g., sodium bicarbonate, potassiumbicarbonate, etc.; alkali metal salts of an organic acid such as analkali metal acetate, e.g., sodium acetate, potassium acetate, etc.; analkali metal alkoxides such as sodium methylate, potassiumtert-butoxide, etc.; organic bases such as trimethylamine,triethylamine, diisopropylethylamine, pyridine, picoline,N-methylpyrrolidine, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-en, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]-7-undecene, etc.; lithium salts such as methyllithium, n-butyrolithium, sec-butyrolithium, tert-butyrolithium, etc.;lithium amides such as lithium diisopropylamide, etc.; and the like.

[0178] This reaction is generally carried out in a solvent. As suchsolvent, the solvents described for Method A are used as such.

[0179] In the reaction, about 0.8 to 10 moles, preferably about 0.9 to 5moles of the compound L¹-Z, and about 1 to about 100 moles, preferablyabout 1 to about 20 moles of the base are used per 1 mole of compound(III).

[0180] The reaction temperature is about −10° C. to about 250° C.,preferably about −5° C. to about 200° C.

[0181] The reaction time varies depending on a kind of compound (III),the compound L¹-Z, the base or the solvent, the reaction temperature,and the like, but is usually about 1 minute to about 200 hours,preferably about 5 minutes to about 100 hours.

[0182] This reaction can be accelerated by using a metal catalyst ifnecessary. As such metal catalyst, for example, there can be used apalladium compound [e.g. palladium acetate,tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladiumchloride, dichlorobis(triethylphosphine)palladium,tris(dibenzylideneacetone)dipalladium-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,etc.], a nickel compound [e.g. tetrakis(triphenylphosphine)nickel,bis(triethylphosphine)nickel chloride, bis(triphenylphosphine)nickelchloride, etc.], a rhodium compound [e.g. tri(triphenylphosphine)rhodiumchloride, etc.], and the like, inter alia, a palladium compound ispreferable. The amount of these catalysts to be used is about 10 to0.000001 mole, preferably about 1 to 0.001 mole per 1 mole of compound(III).

[0183] Further, this reaction may be carried out in a sealed tube.

[0184] Method C

[0185] Compound (I) or a salt thereof can be prepared by reactingcompound (IV) represented by the formula (IV):

[0186] wherein the symbols are as defined above, or a salt thereof witha compound represented by a formula L²-COOR³ wherein the symbols are asdefined above, or a salt thereof.

[0187] In the above-mentioned formula, the leaving group represented byL² denotes a halogen atom, a phenoxy group optionally having asubstituent, an optionally substituted lower (C₁₋₆) alkoxy group, acyano group, an imidazolyl group having a substituent or an imidazoliumgroup.

[0188] This reaction is usually carried out in the presence of a base.As such base, bases described for Method B are used as such.

[0189] This reaction is generally carried out in a solvent. As suchsolvent, solvents described for Method A are used as such.

[0190] In the reaction, about 0.8 to 10 moles, preferably about 0.9 to 5moles of the compound L²-COOR³, and about 1 to about 100 moles,preferably about 1 to about 20 moles of the base are used per 1 mole ofcompound (IV).

[0191] The reaction temperature is about −10° C. to about 250° C.,preferably about −5° C. to about 200° C.

[0192] The reaction time varies depending on a kind of compound (IV),the compound L²-COOR³, the base or the solvent, the reaction temperatureand the like, and is usually about 1 minute to about 200 hourspreferably about 5 minutes to about 100 hours.

[0193] Starting compounds (II), (II) and (IV) which are used in theabove-mentioned preparing Methods A to C can be prepared, for example,by a known per se method or a similar method as shown below.

[0194] Compound (V) represented by the formula (V):

[0195] wherein P¹ denotes a protecting group for the amino group, and R⁴denotes an optionally substituted lower (C₁₋₆) alkyl group, or a saltthereof, is subjected to a reducing reaction to prepare compound (VI)represented by the formula (VI):

[0196] wherein the symbols are as defined above, or a salt thereof, orcompound (VII) represented by the formula (VII):

[0197] wherein the symbols are as defined above, or a salt thereof.

[0198] In the above-mentioned formulas (V), (VI) and (VII), as theprotecting group for the amino group represented by P¹, there can beused, for example, formyl group, a C₁₋₆ alkyl-carbonyl group (e.g.acetyl, ethylcarbonyl etc.), a C₁₋₆ alkyl-sulfonyl group,tert-butyloxycarbonyl group, benzyloxycarbonyl group, allyloxycarbonylgroup, fluorenylmethyloxycarbonyl group, an arylcarbonyl group (e.g.phenylcarbonyl, naphthylcarbonyl, etc.), an arylsulfonyl group (e.g.phenylsulfonyl, naphthylsulfonyl, etc.), a C₁₋₆ alkyloxy-carbonyl group(e.g. methoxycarbonyl, ethoxycarbonyl, etc.), a C₇₋₁₀aralkyl-carbonylgroup (e.g. benzylcarbonyl, etc.), methyl group, an aralkyl group (e.g.benzyl, diphenylmethyl, trityl group, etc.), and the like. These groupsmay be substituted with 1 to 3 halogen atom(s) (e.g. fluorine, chlorine,bromine, etc.), nitro group(s) and the like.

[0199] In this reaction, when compound (V) or a salt thereof issubjected to the reducing reaction to prepare compound (VI), as areducing agent, lithium aluminium hydride, trimethoxylithium aluminiumhydride, tri-tert-butoxylithium aluminium hydride, sodium aluminiumhydride, sodium triethoxyaluminium hydride, sodium borohydride/cobaltchloride and the like are preferably used. Alternatively, a catalyticreducing method using a catalyst may be used. The reaction is carriedout under a hydrogen atmosphere using a catalyst such as a palladiumcatalyst, e.g., palladium black, palladium carbon, palladium-silica gel,palladium-barium sulfate and the like, a platinum catalyst, e.g.,platinum oxide, platinum carbon, platinum black and the like, a rhodiumcatalyst, e.g., rhodium carbon, rhodium alumina and the like, aruthenium catalyst, e.g., ruthenium oxide, ruthenium carbon and thelike, Raney nickel, or the like. An amount of the catalyst to be used isabout 0.0001 to about 2 moles, preferably about 0.001 to about 1 moleper 1 mole of compound (V). In addition, this catalytic reducingreaction is generally carried out under normal pressure, while it mayalso be carried out under pressure if necessary. Such pressure isusually about 1 to about 150 atm, preferably about 1 to about 100 atm.

[0200] This reaction is generally carried out in a solvent, and asolvent which dose not interfere with the reaction is appropriatelyselected. As such solvent, there can be used alcohols such as methanol,ethanol, propanol, isopropanol, butanol, tert-butanol and the like,ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butylmethyl ether, diisopropyl ether, ethylene glycol-dimethyl ether and thelike, esters such as ethyl formate, ethyl acetate, n-butyl acetate andthe like, halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride, trichlene, 1,2-dichloroethane and the like,hydrocarbons such as n-hexane, benzene, toluene and the like, amidessuch as formamide, N,N-dimethylformamide, N,N-dimethylacetamide and thelike, organic acids such as formic acid, acetic acid, trifluoroaceticacid and the like, dimethyl sulfoxide, sulfolane,hexamethylphosphoramide and the like. They can be used alone or as amixed solvent thereof.

[0201] Alternatively, this reaction may be carried out in the presenceof an acid if necessary and, as such acid, mineral acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,perchloric acid and the like, sulfonic acids such as methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,camphorsulfonic acid and the like, and organic acids such as formicacid, acetic acid, propionic acid, trifluoroacetic acid and the like areused. When Raney nickel is used, amines such as ammonia are present inmany cases. An amount of these acids to be used is about 0.01 to about20 moles, preferably about 0.1 to about 10 moles per 1 mole of compound(V).

[0202] The reaction temperature is about −78° C. to about 150° C.,preferably about −30° C. to about 100° C.

[0203] The reaction time varies depending on a kind of compound (V), akind of the solvent and the reaction temperature, and is usually about10 minutes to 72 hours, preferably about 15 minutes to about 48 hours.

[0204] In this reaction, when compound (V) or a salt thereof issubjected to the reduction to prepare carbonyl compound (VII), theiminium salt obtained by using reductant in the presence of acid ishydrolyzed with water. In this reduction, for example, a reaction usingformic acid and Raney nickel may be used. An amount of the catalyst tobe used is about 0.01 to about 20 moles, preferably about 0.1 to about10 mole per 1 mole of compound (V).

[0205] This reaction is generally carried out in a solvent, and asolvent which dose not interfere with the reaction is appropriatelyselected. As such solvent, there can be used alcohols such as methanol,ethanol, propanol, isopropanol, butanol, tert-butanol and the like,ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butylmethyl ether, diisopropyl ether, ethylene glycol-dimethyl ether and thelike, esters such as ethyl formate, ethyl acetate, n-butyl acetate andthe like, halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride, trichlene, 1,2-dichloroethane and the like,hydrocarbons such as n-hexane, benzene, toluene and the like, amidessuch as formamide, N,N-dimethylformamide, N,N-dimethylacetamide and thelike, organic acids such as trifluoroacetic acid and the like, dimethylsulfoxide, sulfolane, hexamethylphosphoramide and the like. They can beused alone or as a mixed solvent thereof.

[0206] Alternatively, this reaction may be carried out in the presenceof an acid if necessary and, as such acid, mineral acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,perchloric acid and the like, sulfonic acids such as methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, toluensulfonic acid,camphorsulfonic acid and the like, and organic acids such as formicacid, acetic acid, propionic acid, trifluoroacetic acid and the like areused. An amount of these acids to be used is about 0.01 to about 20moles, preferably about 0.1 to about 10 moles per 1 mole of compound(V).

[0207] The reaction temperature is about −30° C. to about 150° C.,preferably about 0° C. to about 120° C.

[0208] The reaction time varies depending on a kind of compound (V), akind of the solvent and the reaction temperature, and is usually about10 minutes to 72 hours, preferably about 15 minutes to about 48 hours.

[0209] Method E

[0210] Compound (X) represented by the formula (X):

[0211] wherein the symbols are as defined above, or a salt thereof, canbe prepared by subjecting compound (VI) represented by the formula (VI):

[0212] wherein the symbols are as defined above, or a salt thereof, andcompound (VIII) represented by the formula (VIII):

[0213] wherein P² denotes a protecting group for the amino group, or asalt thereof, to a reductive aminating reaction, or subjecting compound(VII) represented by the formula (VII):

[0214] wherein the symbols are as defined above, or a salt thereof, andcompound (IX) represented by formula (IX):

[0215] wherein P² denotes a protecting group for the amino group, or asalt thereof, to a reductive aminating reaction.

[0216] In the above-mentioned formulas (VIII), (IX) and (X), as theprotecting group for the amino group represented by P², there can beused, for example, formyl group, a C₁₋₆ alkyl-carbonyl group (e.g.acetyl, ethylcarbonyl, etc.), a C₁₋₆ alkyl-sulfonyl group,tert-butyloxycarbonyl group, benzyloxycarbonyl group, allyloxycarbonylgroup, fluorenylmethyloxycarbonyl group, an arylcarbonyl group (e.g.phenylcarbonyl, naphthylcarbonyl, etc.), an arylsulfonyl group (e.g.phenylsulfonyl, naphthylsulfonyl, etc.), a C₁₋₆ alkyloxy-carbonyl group(e.g. methoxycarbonyl, ethoxycarbonyl, etc.), a C₇₋₁₀ aralkyl-carbonylgroup (e.g. benzylcarbonyl, etc.), methyl group, an aralkyl group (e.g.benzyl, diphenylmethyl, trityl group, etc.), and the like are used.These groups may be substituted with 1 to 3 halogen atom (e.g. fluorine,chlorine, bromine, etc.), nitro group(s) and the like.

[0217] As a reducing agent used in this reductive aminating reaction,metal hydride complex compounds such as lithium aluminium hydride,trimethoxylithium aluminium hydride, tri-tert-butoxylithium-aluminiumhydride, sodium aluminium hydride, sodium triethoxyaluminium hydride,sodium borohydride, sodium trimethoxyborohydride, sodiumcyanoborohydride, sodium triacetoxyborohydride, lithium borohydride,lithium cyanoborohydride, lithium triethylborohydride and the like, andtriethylsilane are preferably used. Alternatively, a catalytic reducingmethod using a catalyst may also be used. The reaction is carried outunder a hydrogen atmosphere using as a catalyst such as a palladiumcatalyst, e.g., palladium black, palladium carbon, palladium-silica gel,palladium-barium sulfate and the like, a platinum catalyst, e.g.,platinum oxide, platinum carbon, platinum black and the like, a rhodiumcatalyst, e.g., rhodium carbon, rhodium alumina and the like, aruthenium catalyst, e.g., ruthenium oxide, ruthenium carbon and thelike, Raney nickel and the like. An amount of the catalyst is about0.0001 to about 2 moles, preferably about 0.001 to about 1 mole per 1mole of compound (VI) or compound (VII). In addition, this catalyticreducing reaction is generally carried out at normal pressure, while itmay also be carried out under pressure if necessary. Such pressure isusually about 1 to about 150 atm, preferably about 1 to about 100 atm.

[0218] This reaction is generally carried out in a solvent, and asolvent which dose not interfere with the reaction is appropriatelyselected. As such solvent, there can be used alcohols such as methanol,ethanol, propanol, isopropanol, butanol, tert-butanol and the like,ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butylmethyl ether, diisopropyl ether, ethylene glycol-dimethyl ether and thelike, esters such as ethyl formate, ethyl acetate, n-butyl acetate andthe like, halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride, trichlene, 1,2-dichloroethane and the like,hydrocarbons such as n-hexane, benzene, toluene and the like, amidessuch as formamide, N,N-dimethylformamide, N,N-dimethylacetamide and thelike, organic acids such as formic acid, acetic acid, trifluoroaceticacid and the like, dimethyl sulfoxide, sulfolane,hexamethylphosphoramide and the like. They are used alone or as a mixedsolvent thereof.

[0219] Alternatively, this reaction may be carried out in the presenceof an acid if necessary and, as such acid, mineral acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,perchloric acid and the like, sulfonic acids such as methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,camphorsulfonic acid and the like, and organic acids such as formicacid, acetic acid, propionic acid, trifluoroacetic acid and the like areused. An amount of these acids to be used is about 0.01 to about 20moles, preferably about 0.1 to about 10 moles per 1 mole of compound(VI) or compound (VII).

[0220] The reaction temperature is about −30° C. to about 150° C.,preferably about −10° C. to 120° C.

[0221] The reaction time varies depending on a kind of compounds (VI) to(IX), a kind of the solvent and the reaction temperature, and is usuallyabout 10 minutes to about 72 hours, preferably about 15 minutes to about48 hours.

[0222] Method F

[0223] Compound (XII) of the formula (XII):

[0224] wherein the symbols are as defined above, or a salt thereof canbe prepared by subjecting compound (X) represented by the formula (X):

[0225] wherein the symbols are as defined above, or a salt thereof, andcompound (XI) represented by the formula (XI):

[0226] wherein L³ and L⁴ denote a leaving group, or a salt thereof, toamidating reaction, followed by subjecting to cyclizing reaction.

[0227] In the above formula (XI), the leaving group represented by L³denotes, for example, a halogen atom, a group represented by the formulaR⁸—SO₂—O— (wherein R⁸ denotes a lower alkyl group optionally substitutedwith a halogen atom or a phenyl group optionally having a substituent(e.g. the same group as a lower alkyl group optionally substituted witha halogen atom or a phenyl group optionally having a substituentrepresented by R⁷)), or the like. In addition, a part represented byCOL⁴ in compound (XI) represents a free acid or a salt thereof(inorganic salt, organic salt etc.) or a reactive derivative thereof(e.g. acid halide, ester, acid azide, acid anhydride, mixed acidanhydride, active amide, active ester, active thioester etc.).

[0228] Examples of a salt of compound (X) include acid addition saltswith the above-mentioned acids which form an acid addition salt withcompound (I).

[0229] As an inorganic salt used in compound (XI), alkali metal salts(e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts(e.g. calcium salt, etc.) and the like are used and, as an organic salt,for example, trimethylamine salt, triethyamine salt,tert-butyldimethylamine salt, dibenzylmethylamine salt,benzyldimethylamine salt, N,N-dimethylaniline salt, pyridine salt,quinoline salt and the like are used. In addition, examples of acidhalide include acid chloride, acid bromide and the like;, examples ofthe ester include lower alkyl esters such as those with methyl, ethyland the like, examples of the mixed acid anhydride include mono C₁₋₄alkylcarbonic acid mixed acid anhydride (e.g. mixed acid anhydride offree acid (XI) with monomethylcarbonic acid, monoethylcarbonic acid,monoisopropylcarbonic acid, monoisobutylcarbonic acid, monotert-butylcarbonic acid, monobenzylcarbonic acid,mono(p-nitrobenzyl)carbonic acid, monoallylcarbonic acid, etc.), C₁₋₆aliphatic carbonic acid mixed acid anhydride (e.g. mixed acid anhydrideof free acid (XI) with acetic acid, cyanoacetic acid, propionic acid,butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalicacid, trifluoroacetic acid, trichloroacetic acid, acetoacetic acid,etc.), C₇₋₁₁ aromatic carboxylic acid mixed acid anhydride (e.g. mixedacid anhydride of free acid (XI) with benzoic acid, p- toluic acid,p-chlorobenzoic acid, etc.), organic sulfonic acid mixed acid anhydride(mixed acid anhydride with methanesulfonic acid, ethenesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, etc.), and the like; andexamples of the active amide include an amide with a nitrogen-containingheterocyclic compound (e.g. acid amide of free acid (XI) with pyrazole,imidazole, benzotriazole or the like, and these nitrogen-containingheterocyclic compounds may be substituted with C₁₋₆ alkyl (e.g. methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.),C₁₋₆ alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,tert-butoxy, etc.), halogen atom (e.g. fluorine, chlorine, bromine,etc.), oxo, thioxo, C₁₋₆ alkylthio (e.g. methylthio, ethylthio,propylthio, butylthio, etc.) or the like), and the like.

[0230] Examples of the active ester include, in addition to an organicphosphoric acid ester (e.g. diethoxy phosphoric acid ester,diphenoxyphosphoric acid ester, etc.), p-nitrophenyl ester,2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester,N-hydroxysuccineimide ester, N-hydroxyphthalimide ester,1-hydroxybenzotriazole ester, 6-chloro-1-hydroxybenzotriazole ester,1-hydroxy-1H-2-pyridone ester and the like. Examples of the activethioester include esters with aromatic heterocyclic thiol compounds[these heterocyclic rings may be substituted with C₁₋₆ alkyl (e.g.methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, etc.), C₁₋₆ alkoxy (e.g. methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy, etc.), halogen atom (e.g. fluorine,chlorine, bromine, etc.), C₁₋₆ alkylthio (e.g. methylthio, ethylthio,propylthio, butylthio, etc.) or the like] [e.g. 2-pyridylthiol ester,2-benzothiazolylthiol ester], and the like.

[0231] This reaction is generally carried out in a solvent, ifnecessary, in the presence of a base or a condensing agent (e.g.carbodiimides (DCC, WSC, DIC, etc.), or a phosphoric acid derivative(e.g. diethyl cyanophosphate, DPPA, BOP-Cl, etc.), etc.). As suchsolvent and base, solvents and bases described in the above-mentionedMethod A are used as such.

[0232] In this reaction, about 1 to about 5 moles, preferably about 1 toabout 2 moles of a base is used per 1 mole of compound (X).

[0233] The reaction temperature is about −50° C. to about 150° C.,preferably about −20° C. to about 100° C.

[0234] The reaction time varies depending on a kind of compound (X) or(XI), a kind of the solvent and base, the reaction temperature and thelike, and is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

[0235] The intramolecular cyclizing reaction to be carried out after theamidating reaction is generally carried out in a solvent in the presenceof a base and, as such solvent and base, solvents and bases described inthe above-mentioned Method A are used as such.

[0236] In the reaction, about 1 to about 5 moles, preferably about 1 toabout 2 moles of a base is used per 1 mole of an amide compound.

[0237] The reaction temperature is about −50° C. to about 100° C.,preferably about −20° C. to about 50° C.

[0238] The reaction time varies depending on a kind of the amidecompound, a kind of the solvent and the base, the reaction temperatureand the like, and is usually about 1 minute to about 100 hours,preferably about 15 minutes to about 48 hours.

[0239] Method G

[0240] An ester group of compound (XII) represented by the formula(XII):

[0241] wherein the symbols are as defined above, or a salt thereof, canbe hydrolyzed to prepare compound (XIII) represented by the formula(XIII):

[0242] wherein the symbols are as defined above. or a salt thereof.

[0243] This method is an ester hydrolyzing reaction, and is carried outby appropriately using hydrolysis with an acid or an alkali,hydrogenolysis, or a method using a metal catalyst such as palladiumdepending on R⁴ in compound (XII).

[0244] As the alkali used in this ester hydrolyzing reaction, alkalimetal hydroxides such as lithium hydroxide, sodium hydroxide, potassiumhydroxide, barium hydroxide, calcium hydroxide and the like arepreferably used. In addition, as the acid used in this ester hydrolyzingreaction, for example, mineral acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid,perchloric acid and the like, sulfonic acids such as methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,camphorsulfonic acid and the like, organic acids such as formic acid,acetic acid, propionic acid, trifluoroacetic acid and the like arepreferably used. Alternatively, a catalytic reducing method using acatalyst under a hydrogen atmosphere may also be used. The reaction iscarried out under a hydrogen atmosphere using a catalyst such as apalladium catalyst, e.g., palladium black, palladium carbon,palladium-silica gel, palladium-barium sulfate and the like, a platinumcatalyst, e.g., platinum oxide, platinum carbon, platinum black and thelike, a rhodium catalyst, e.g., rhodium carbon, rhodium alumina and thelike, a ruthenium catalyst, e.g., ruthenium oxide, ruthenium carbon andthe like, Raney nickel or the like. An amount of the catalyst to be usedis about 0.0001 to about 2 moles, preferably about 0.001 to about 1 moleper 1 mole of compound (XII). In addition, this catalytic reducingreaction is generally carried out at normal pressure, while it may alsobe carried out under pressure if necessary. Such pressure is usuallyabout 1 to 150 atm, preferably about 1 to about 100 atm. In addition, inthe case of an allyl ester, it can be converted into carboxylic acid ora salt thereof using a palladium catalyst.

[0245] This reaction is generally carried out in a solvent, and asolvent which dose not interfere with the reaction is appropriatelyselected. As such solvent, there can be used, for example, water,alcohols such as methanol, ethanol, propanol, isopropanol, butanol,tert-butanol and the like, ethers such as dioxane, tetrahydrofran,diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethyleneglycol-dimethyl ether and the like, halogenated hydrocarbons such aschloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane and thelike, hydrocarbons such as n-hexane, benzene, toluene and the like,amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamideand the like, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide andthe like. They are used alone or as a mixed solvent thereof.

[0246] The reaction temperature is about −30° C. to about 150° C.,preferably about −10° C. to about 120° C.

[0247] The reaction time varies depending on a kind of compound (XII), akind of the solvent and the reaction temperature, and is usually about10 minutes to about 72 hours, preferably about 15 minutes to about 48hours.

[0248] Method H

[0249] Compound (XIV) represented by the formula (XIV):

[0250] wherein the symbols are as defined above, or a salt thereof, canbe prepared by converting a carboxylic acid compound (XIII) representedby the formula (XIII):

[0251] wherein the symbols are as defined above, or a salt thereof, intoan acid azide, followed by a thermal rearrangement reaction to obtain anisocyanate, which is reacted with alcohols.

[0252] As an inorganic salt used in compound (XIII), alkali metal salts(e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts(e.g. calcium salt, etc.) and the like are used. As an organic salt, forexample, trimethylamine salt, triethylamine salt,tert-butyldimethylamine salt, dibenzylmethylamine salt,benzyldimethylamine salt, N,N-dimethyaniline salt, pyridine salt,quinoline salt and the like are used.

[0253] Compound (XIII) can be directly converted into an acid azide froma free acid or a salt thereof by reacting with DPPA in the presence of abase. Alternatively, compound (XIII) can be indirectly converted into anacid azide from a free acid or a salt by converting into a reactivederivative of the carboxylic acid, and reacting the derivative with anazidizing reagent such as sodium azide in the presence of a base.Examples of such reactive derivative of the carboxylic acid include acidhalide (e.g. acid chloride, acid bromide, etc.), mixed acid anhydride[mono C₁₋₄ alkylcarbonic acid mixed acid anhydride (e.g. mixed acidanhydride of free acid (XIII) with monomethylcarbonic acid,monoethylcarbonic acid, monoisopropylcarbonic acid, monoisobutylcarbonicacid, mono tert-butylcarbonic acid, monobenzylcarbonic acid, mono(p-nitrobenzyl)carbonic acid, monoallylcarbonic acid etc.), C₁₋₆aliphatic carboxylic acid mixed acid anhydride (e.g. mixed acidanhydride of free acid (XIII) with acetic acid, cyanoacetic acid,propionic acid, butyric acid, isobutyric acid, valeric acid, isovalericacid, pivalic acid, trifluoroacetic acid, trichloroacetic acid,acetoacetic acid, etc.), C₇₋₁₁ aromatic carboxylic acid mixed acidanhydride (e.g. mixed acid anhydride of free acid (XIII) with benzoicacid, p- toluic acid, p-chlorobenzoic acid, etc.), organic sulfonic acidmixed acid anhydride (e.g. mixed acid anhydride with methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonicacid, etc.), etc], active amide [amide with a nitrogen-containingheterocyclic compound (e.g. acid amide of free acid (XIII) withpyrazole, imidazole, benzotriazole, etc.), these nitrogen-containingheterocyclic compounds may be substituted with C₁₋₆ alkyl (e.g. methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.),C₁₋₆ alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,tert-butoxy, etc.), halogen atom (e.g. fluorine, chlorine, bromine,etc.), oxo, thioxo, C₁₋₆ alkylthio (e.g. methylthio, ethylthio,propylthio, butylthio, etc.), etc. ), etc.], active ester [e.g. inaddition to organic phosphoric acid ester (e.g. diethoxyphosphoric acidester, diphenoxyphosphoric acid ester, etc.), p-nitrophenyl ester,2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester,N-hydroxysuccinimide ester, N-hydroxyphthalimide ester,1-hydroxybenzotriazole ester, 6-chloro-1-hydroxybenzotriazole ester,1-hydroxy-1H-2-pyridone ester, etc.], active thioester [ester witharomatic heterocyclic thiol compound [these heterocyclic rings may besubstituted with C₁₋₆ alkyl (e.g. methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, etc.), C₁₋₆ alkoxy (e.g.methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.),halogen atom (e.g. fluorine, chlorine, bromine, etc.), C₁₋₆ alkylthio(e.g. methylthio, ethylthio, propylthio, butylthio, etc.), etc.] [e.g.2-pyridylthiol ester, 2-benzothiazolylthiol ester], etc.].

[0254] This acid azidizing reaction is generally carried out in asolvent and, if necessary, in the presence of a base or a condensingagent (e.g. carbodiimides (DCC, WSC, DIC etc.), a phosphoric acidderivative (e.g. diethyl cyanophosphate, DPPA, BOP-Cl, etc.), etc.). Assuch solvent and base, solvents and bases described in theabove-mentioned Method A are used as such.

[0255] In the reaction, about 1 to about 5 moles, preferably about 1 toabout 2 moles of an azidizing reagent is used per 1 mole of Compound(XIII).

[0256] The reaction temperature is about −50° C. to about 150° C.,preferably about −20° C. to about 100° C.

[0257] The reaction time varies depending on a kind of Compound (XIII),a kind of the solvent and the base, the reaction temperature and thelike, and is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

[0258] The rearrangement reaction into the isocyanate to be carried outafter the acid azidizing reaction is generally carried out in a solventand, as such solvent, solvents and bases described in theabove-mentioned Method A are used as they such. In addition, by adding acorresponding alcohol as a solvent or a reagent during thisrearrangement reaction into the isocyanate, carbamate compound (XIV) canbe prepared without isolating the isocyanate.

[0259] This carbamating reaction is carried out in the presence of abase in many cases, and about 1 to 5 moles, preferably about 1 to about2 moles of a base is used per 1 mole of the isocyanate compound.

[0260] The reaction of rearranging the acid azide into the isocyanategenerally requires heat, and the reaction temperature is about 50° C. toabout 150° C., preferably about 70° C. to about 100° C. In addition, inthe reaction from the isocyanate to the carbamate, the reactiontemperature is about −10° C. to about 150° C., preferably about 0° C. toabout 100° C.

[0261] These reaction times vary depending on a kind of the acid azideand the isocyanate compound, a kind of the solvent and the base, and thereaction temperature and the like, and are usually about 1 minute toabout 100 hours, preferably about 15 minutes to about 48 hours.

[0262] Method I

[0263] Compound (XV) represented by the formula (XV):

[0264] wherein the symbols are as defined above, or a salt thereof, orcompound (XVI) represented by the formula (XVI):

[0265] wherein the symbols are as defined above, or a salt thereof, canbe prepared by selectively deprotecting a protecting group for the aminogroup in compound (XIV) represented by the formula (XIV):

[0266] wherein the symbols are as defined above, or a salt thereof.

[0267] As a method for selectively removing a protecting group for theamino group, a known per se method or a similar method can be used and,for example, a method using an acid (hydrochloric acid, hydrobromicacid, trifluoroacetic acid, hydrogen fluoride, etc.), a base (amine,hydrazine, sodium hydroxide, etc.), reduction (hydrogenative degradationand catalytic reduction using a catalyst, zinc in the presence of anacid, etc.), ultraviolet-ray, palladium acetate, trimethylsilyl iodide,1-chloroethyl chlorocarbonate/methanol and the like are used.

[0268] Compound (II) represented by the formula (II):

[0269] wherein the symbols are as defined above, or a salt thereof, canbe prepared by reacting compound (XV) represented by the formula (XV):

[0270] wherein the symbols are as defined above above, or a saltthereof, with L¹-Z by the method shown in Method B, and subsequentlydeprotecting the protecting group P² by the method shown in Method I.

[0271] Further, compound(III) represented by the formula (III):

[0272] wherein the symbols are as defined above, or a salt thereof, canbe prepared by reacting compound (XVI) represented by the formula (XVI):

[0273] wherein the symbols are as defined above, or a salt thereof, withR¹SO₂-Q by the method shown in Method A, and subsequently deprotectingthe protecting group P¹ by the method shown in Method I.

[0274] Compound (IV) represented by the formula (IV):

[0275] wherein the symbols are as defined above, or a salt thereof, canbe prepared by deprotecting the carbamate-type protective group ofcompound (I) represented by the formula (I):

[0276] wherein the symbols are as defined above, or a salt thereof, by aknown per se method and, specifically, the method of Method Icorresponds thereto.

[0277] Starting compounds (V), (VIII), (IX) and (XI) used in theabove-mentioned preparing Methods D to F can be prepared by a known perse method or a similar method.

[0278] When a compound is obtained in the free form by each reaction ofthe present invention, it may be converted into a salt according to aconventional method and, when obtained as a salt, it may be convertedinto a free compound or another salt according to a conventional method.

[0279] The thus-obtained compound (I) can be isolated and purified froma reaction mixture by a known per se means, for example, means such asextraction, concentration, neutralization, filtration,recrystallization, column chromatography, thin layer chromatography andthe like.

[0280] A salt of compound (I) can be prepared by according to a knownper se means, for example, by adding an inorganic acid or an organicacid to compound (I).

[0281] When there are stereo isomers in compound (I), these individualisomers and a mixture thereof are all included naturally in the scope ofthe present invention, and these isomers can be optionally preparedindividually, if necessary.

[0282] In addition, compound (I) or a salt thereof may be a hydrate, andboth hydrate and non-hydrate are all included in the scope of thepresent invention.

[0283] Since compound (I) according to the present invention or a saltthereof has a low toxicity and is safe and it inhibits an FXa and has ananticoagulative effect, it is useful in preventing and/or treatingdiseases, for example, cardiac infarction, cerebral thrombosis, deepvein thrombosis, pulmonary thromboembolism, thromboembolism during orafter surgery, economy-class syndromes, inflammation, cancers, etc., aswell as those listed below in animals especially in mammals (forexample, human, monkey, cat, pig, horse, cattle, mouse, rat, guinea pig,dog, rabbit, etc.), and is preferred especially when being used inpreventing and/or treating cardiogenic embolus such as atrialfibrillation, etc., cerebral infarction due to embolus derived fromarteriosclerotic lesion at carotid, etc., deep vein thrombosis,pulmonary thromboembolism, and the like.

[0284] Brain:

[0285] cerebral embolus, cerebral infarction due to atrial fibrillation,acute ischemic cerebral apoplexy, acute cerebral thrombosis, cerebralvascular contraction after subarachnoidal hemorrhage, Alzheimer'sdisease, transient ischemic attack (TIA), mixed dementia, cerebralvascular/multiple infarction dementia,

[0286] Heart:

[0287] acute coronary disease, acute cardiac infarction, cardiacinfarction sequela, improvement of prognosis of cardiac infarctionand/or prevention of secondary sideration of cardiac infarction,unstable angina, angina, vascular reocculusion and stenosis aftercoronary intervention such as stent indwelling or implementation of PTCA(percutaneous coronary angioplasty) and atherectomy,

[0288] Periphery:

[0289] deep vein thrombosis, prevention of sideration and secondarysideration of deep vein thrombosis, chronic arterial occulusion,peripheral vascular disease, adult respiratory distress syndrome,chronic renal disease (e.g. diabetic nephropathy, chronicglomerulonephritis, IgA nephropathy, etc.), diabetic circulationdisorder, pain, neural disorder,

[0290] Others:

[0291] platelet reduction due to dialysis, platelet reduction at severeoperation, atherosclerosis, cancer metastasis, systemic inflammatoryresponse syndrome (SIRS) or disseminated intravascular coagulationsyndrome (DIS), congestive chronic heart failure, rejection reaction attransplantation, organ protection or function improvement attransplantation, various organ failures generated by shock orprogression of DIC (e.g. pulmonary failure, hepatic failure, renalfailure, heart failure etc.), prevention of coagulation of perfusingblood at blood extracorporeal circulation.

[0292] Compound (I) of the present invention or a salt thereof canorally or parenterally be administered as it is or in combination with apharmaceutically acceptable carrier.

[0293] A formulation containing compound (I) or a salt thereof can begiven orally in a dosage form such as tablets (including sugar-coatedtablets and film-coated tablets), pills, granules, powders, capsules(including soft capsules, microcapsules), syrups, emulsions andsuspensions, while it can be given parenterally in a dosage form such asinjection, infusion and dripping formulations as well as suppositories.Further, a sustained release preparation prepared by combining with asuitable base (e.g., a polymer of butyric acids, a polymer of glycolicacids, a copolymer of butyric acid-glycolic acid, a mixture of a polymerof butyric acids and a polymer of glycolic acids, a polyglycerol fattyacid ester, etc.) is also advantageous.

[0294] While the amount of compound (I) or a salt thereof in aformulation of the present invention may vary depending on the form ofthe formulation, it is usually 2 to 85% by weight, preferably 5 to 70%by weight based on the entire amount of the formulation.

[0295] A method for formulating compound (I) or a salt thereof into adosage form described above, a known method which is generally employedin the art can be applied. Also for producing a dosage form describedabove, appropriate amounts of appropriate additives employed usually inthe pharmaceutical field such as excipients, binders, disintegrants,lubricants, sweeteners, surfactants, suspending agents, emulsifiers andthe like can be incorporated.

[0296] For example, compound (I) or a salt can be formulated into atablet by incorporating an excipient, a binder, a disintegrant, alubricant and the like, while it can be formulated into a pill or agranule by incorporating an excipient, a binder, a disintegrant and thelike. It can be formulated also into a powder or a capsule byincorporating an excipient, into a syrup by incorporating a sweetener,into an emulsion or a suspension by incorporating a suspending agent, asurfactant, an emulsifier, and the like.

[0297] An excipient may, for example, be lactose, sugar, glucose,starch, sucrose, microcrystalline cellulose, licorice powder, mannitol,sodium hydrogen carbonate, calcium phosphate, calcium sulfate, and thelike.

[0298] A binder may, for example, be 5 to 10% by weight starch glue, 10to 20% by weight gum arabic or gelatin solution, 1 to 5% by weighttragacanth gum solution, carboxymethyl cellulose solution, sodiumalginate solution glycerin, and the like.

[0299] A disintegrant may, for example, be a starch, calcium carbonate,and the like.

[0300] A lubricant may, for example, be magnesium stearate, stearicacid, calcium stearate, purified talc, and the like.

[0301] A sweetener may, for example, be glucose, fructose, invertedsugar, sorbitol, xylitol, glycerin, syrups simplex, and the like.

[0302] A surfactant may, for example, be sodium lauryl sulfate,polysorbate 80, sorbitan monofatty ester, polyoxyl stearate 40, and thelike.

[0303] A suspending agent may, for example, be gum arabic, sodiumalginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite,and the like.

[0304] An emulsified may, for example, be gum arabic, tragacanth gum,gelatin, polysorbate 80, and the like.

[0305] Also for formulating compound (I) or a salt thereof into a dosageform described above, appropriate amounts of appropriate additivesemployed usually in the pharmaceutical field such as colorants,preservatives, flavors, seasonings, corrigents, stabilizers, thickeningagents, and the like can be incorporated, if necessary.

[0306] A formulation according to the present invention containingcompound (I) or a salt thereof is stable and has low toxicity, and canbe used safely. Its daily dose may varies depending on the condition andthe body weight of a patient, the type of the compound and theadministration route, and is usually about 1 to 1000 mg as an activeingredient (compound (I) or a salt thereof) per day in an adult weighingabout 60 kg when given orally to a patient having a thrombosis,preferably about 3 to 300 mg, more preferably about 10 to 200 mg, whichcan be given at once, or divided into two or 3 dosages.

[0307] When compound (I) of the present invention or a salt thereof isgiven parenterally, it is given usually in a liquid formulation (forexample, injection formulation). In such case, a single dosage may varydepending on the target organ, the condition and the administrationmode, and is usually about 0.01 mg to about 100 mg per kg body weightwhen given in the form of an injectable preparation, preferably about0.01 to about 50 mg, more preferably about 0.01 to about 20 mg, which isgiven conveniently via intravenous injection. In addition to theintravenous injectable preparation, a subcutaneous injectablepreparation, an intradermal injectable preparation, an intramuscularinjectable preparation and a dripping injectable preparation may alsoincluded in the injection formulation, and an iontophoresis percutaneousformulation is included in a sustained release formulation. Any of suchinjection formulations can be prepared by a method known per se, i.e.,by dissolving, suspending or emulsifying compound (I) of the presentinvention or a salt thereof in an aseptic aqueous or oily liquid. Anaqueous liquid for injection may for example be a physiological salineand an isotonic solution containing glucose or other auxiliary agents(for example, D-sorbitol, D-mannitol, sodium chloride and the like),which may be used in combination with a suitable solubilizing aid suchas an alcohol (for example, ethanol), a polyalcohol (for example,propylene glycol, polyethylene glycol), a nonionic surfactant (forexample, polysorbate 80, HCO-50), and the like. An oily liquid may, forexample, be a sesame oil, a soybean oil, etc., which may be used incombination with a solubilizing aid such as benzyl benzoate, benzylalcohol, etc. Those which may also be incorporated are a buffering agent(for example, phosphate buffer and sodium acetate buffer), an analgesic(for example, benzalkonium chloride, procaine hydrochloride, etc.), astabilizer (for example, human serum albumin, polyethylene glycol,etc.), a preservative (for example, benzyl alcohol, phenol, etc.), andthe like. The injection formulation thus prepared is contained usuallyin an ampule.

[0308] The formulation of the present invention may appropriately beused in combination with a thrombolytic agent (for example, TPA,urokinase. etc.), an Alzheimer treating agent (for example, Avan, Calan,etc.), a cholesterol treating agent (for example, HMG-CoA reductaseinhibitor such as simvastatin, pravastatin, etc.), a TG reducing agent(for example, clofibrate, etc.), an AII antagonist (for example,candesartan, cilexetil, losartan, etc.), an antiplatelet agent (forexample, clopidogrel, abciximab, aspirin, etc.), a Ca antagonist (forexample, calslot, amlodipine, etc.), an ACE inhibitor (for example,enalapril, captopril, etc.), a β blocker (for example, metoprolol,carvedilol, etc.), an antiarrhythmic agent (for example, procaine amide,etc.), and the like, or these medicinal components can appropriatelyformulated in a preparation.

[0309] The present invention is further detailed in the followingReference Examples, Examples, Formulation Examples and Experiments,which serve only as examples and are not intended to restrict thepresent invention and can be modified without departing the scope of thepresent invention.

[0310] Elution of a column chromatography in Reference Examples andExamples was conducted with observing by TLC (thin layerchromatography). In the observation of TLC, a TLC plate employed was a60F254 manufactured by Merck, and the plate was developed with a solventwhich was employed as an eluent in a column chromatography, while an UVdetector was used for detection. Silica gel employed was kieselgel 60(70 to 230 mesh) manufactured by Merck. NMR spectra were recorded on aGemini 200 spectrometer using tetramethylsilane as an internal orexternal standard and the chemical shift data were represented in δvalues (ppm). IR spectra were determined on a Shimadzu FTZR-8200spectrometer. The figure in a bracket indicated in conjunction with amixed solvent is a volume ratio of the constituent solvents. The percentindicated in conjunction with a solution is the amount in gram containedin 100 ml of the solution. The following abbreviations are employed inReference Examples and Examples.

[0311] s: singlet

[0312] d: doublet

[0313] t: triplet

[0314] q: quartet

[0315] quint: quintet

[0316] ABq: AB type quartet

[0317] dd: double doublet

[0318] m: multiplet

[0319] br: broad

[0320] brs: broad singlet

[0321] J: coupling constant

[0322] WSC: water-soluble carbodiimide

[0323] THF: tetrahydrofuran

[0324] DMF: dimethylformamide

[0325] DMSO: dimethylsulfoxide

[0326] Fmoc: 9-fluorenylmethoxycarbonyl

[0327] HOBt: 1-hydroxybenzotriazole

REFERENCE EXAMPLE 14-Benzyloxycarbonyl-1-[1,4-bis(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone

[0328] An aqueous solution (400 ml) of sodium carbonate (31.8 g) andcarbobenzoxy chloride (51.2 g) were added to a solution of2,2-diethoxyethylamine (42.0 g) in ethyl acetate (300 ml) underice-cooling, and the mixture was stirred for 6 hours. After separatingthe mixture into layers, the organic layer was washed successively with0.5N hydrochloric acid, an aqueous sodium bicarbonate solution and anaqueous saturated sodium chloride solution, dried and concentrated togive pale orange oily benzyl 2,2-diethoxyethylcarbamate (78.6 g).

[0329]¹H-NMR (CDCl₃) δ: 1.20 (6H, t, J=7.0 Hz), 3.33 (2H, t, J=5.7 Hz),3.40-3.80 (4H, m), 4.50 (1H, t, J=5.3 Hz), 4.90 (1H, br), 5.11 (2H, s),7.30-7.45 (5H, m).

[0330] To a solution of benzyl 2,2-diethoxyethylcarbamate (45.4 g) inacetone (260 ml) was added 1N Hydrochloric acid (130 ml), and themixture was stirred at 60° C. for 40 minutes. An aqueous saturatedsodium bicarbonate solution was added to the reaction solution, followedby extraction with ethyl acetate. The organic layer was washed with anaqueous saturated sodium chloride solution, dried and concentrated. Theresulting oil (37.7 g) was dissolved in THF (600 ml), tert-butyl1-(tert-butoxycarbonyl)-4-aminomethylisonipecotinate (37.7 g), aceticacid (6.87 ml) and sodium triacetoxyborohydride (36.0 g) were addedthereto, and the mixture was stirred at room temperature for 3 days. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane:ethylacetate=2:1→0:1) to obtain pale yellow oily tert-butyl1-(tert-butoxycarbonyl)-4-[N-[2-[N-(benzyloxycarbonyl)amino]ethyl]aminomethyl]-isonipecotinate.

[0331]¹H-NMR (CDCl₃) δ: 1.20-1.60 (2H, m), 1.44 (9H, s), 1.45 (9H, s),1.95-2.10 (2H, m), 2.64 (2H, s), 2.71 (2H, t, J=5.7 Hz), 2.85-3.05 (2H,m), 3.24 (2H, q, J=4.3 Hz), 3.75-3.95 (2H, m), 5.09 (2H, s), 5.05-5.25(1H, m), 7.30-7.40 (5H, m).

[0332] tert-Butyl1-(tert-butoxycarbonyl)-4-[N-[2-[N-(benzyloxycarbonyl)amino]ethyl]aminomethyl]isonipecotinate(40.4 g) was dissolved in ethyl acetate (300 ml) and THF (100 ml),triethylamine (17.2 ml) was added, and then a solution of chloroacetylchloride (7.85 ml) in ethyl acetate (50 ml) was added dropwise theretoat 0° C. After stirring at 0° C. for 30 minutes, water was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was washed with 5% aqueous citric acid, an aqueous saturatedsodium bicarbonate solution and an aqueous saturated sodium chloridesolution, dried and concentrated. The resulting residue (46.6 g) wasdissolved in DMF (450 ml), sodium hydride (3.60 g) was added underice-cooling, and the mixture was stirred at room temperature for 3 days.After the reaction solution was concentrated under reduced pressure,ethyl acetate was added thereto, the solution was washed with water andan aqueous saturated sodium chloride solution, dried, and concentrated.The residue was subjected to silica gel column chromatography(hexane:ethyl acetate=2:1→0:1) to obtain the title compound (35.3 g) asan orange syrup.

[0333]¹H-NMR (CDCl₃) δ: 1.30-1.60 (2H, m), 1.44 (9H, s), 1.47 (9H, s),1.90-2.10 (2H, m), 2.70-3.00 (2H, m), 3.20-4.10 (8H, m), 4.15 (2H, s),5.15 (2H, s), 7.30-7.40 (5H, m).

REFERENCE EXAMPLE 21-(tert-Butoxycarbonyl)-4-[4-(6-chloro-2-naphthalenesulfonyl)-2-oxo-1-piperazinylmethyl]isonipecotinicAcid REFERENCE EXAMPLE 2-11-[1,4-Bis(tert-butoxycarbonyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone

[0334]4-Benzyloxycarbonyl-1-[1,4-bis(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone(35 g) was dissolved in ethanol (400 ml), 10% palladium carbon (5.0 g)was added, and the mixture was vigorously stirred for 1 hour under ahydrogen stream. After the catalyst was removed, the solvent wasdistilled off under reduced pressure. The resulting residue wasdissolved in ethyl acetate (300 ml), an aqueous solution (200 ml) ofsodium carbonate (10.5 g), and a solution of6-chloronaphthalene-2-sulfonyl chloride (18.9 g) in ethyl acetate 100ml) were added at 0° C. After stirring at 0° C. for 2 hours, the organiclayer was separated, washed with an aqueous saturated sodium chloridesolution, dried, and concentrated. The residue was subjected to silicagel column chromatography (ethyl acetate:methanol=1:1) to obtain theamorphous title compound (33.5 g).

[0335]¹H-NMR (CDCl₃) δ: 1.25-1.50 (2H, m), 1.42 (9H, s), 1.44 (9H, s),1.80-2.00 (2H, m), 2.68-2.90 (2H, m), 3.26-3.70 (6H, m), 3.77 (2H, s),3.70-4.00 (2H, m), 7.61 (1H, dd, J=8.9, 1.9 Hz), 7.78 (1H, dd, J=8.6,1.8 Hz), 7.91-7.98 (3H, m), 8.34 (1H, d, J=1.4 Hz).

REFERENCE EXAMPLE 2-21-(tert-Butoxycarbonyl)-4-[4-(6-chloro-2-naphthalenesulfonyl)-2-oxo-1-piperazinylmethyl]isonipecotinicAcid

[0336] Trifluoroacetic acid (100 ml) was added to a solution of1-[1,4-bis(tert-butoxycarbonyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone(36.5 g) in toluene (100 ml), and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated, THF (200ml), 1N sodium hydroxide (500 ml), and di-tert-butyl dicarbonate (17.6g) were added to the resulting residue, and the mixture was stirred atroom temperature for 4 hours. Acetic acid (30 ml) was added to thereaction mixture to adjust to weak acidic, and the mixture was extractedwith ethyl acetate. The organic layer was washed with an aqueoussaturated sodium chloride solution, dried, and concentrated. Theprecipitated crystals were washed with ether to obtain the titlecompound (23.7 g) as colorless crystals.

[0337]¹H-NMR (CDCl₃) δ: 1.20-1.50 (2H, m), 1.44 (9H, s), 1.90-2.08 (2H,m), 2.65-2.95 (2H, m), 3.30-3.70 (6H, m), 3.75-4.10 (2H, m), 3.82 (2H,s), 7.58 (1H, dd, J=8.8, 2.0 Hz), 7.80 (1H, dd, J=8.6, 1.6 Hz),7.86-8.00 (3H, m), 8.39 (1H, s).

REFERENCE EXAMPLE 31-(tert-Butoxycarbonyl)-4-[2-oxo-4-(4-vinylbenzenesulfonyl)-1-piperazinylmethyl]isonicopetinicAcid

[0338] According to the same manner as that of Reference Example 2except that 4-vinylbenzenesulfonyl chloride was used in place of6-chloronaphthalene-2-sulfonyl chloride, the colorless amorphous titlecompound was obtained.

[0339]¹H-NMR (CDCl₃) δ: 1.20-1.50 (2H, m), 1.44 (9H, s), 1.95-2.10 (2H,m), 2.70-3.00 (2H, m), 3.20-3.80 (6H, m), 3.76 (2H, s), 3.80-4.10 (2H,m), 5.47 (1H, d, J=10.8 Hz), 5.91 (1H, d, J=17.6 Hz), 6.76 (1H, dd,J=17.6, 10.8 Hz), 7.58 (2H, d, J=8.5 Hz), 7.76 (2H, d, J=8.5 Hz).

REFERENCE EXAMPLE 41-(tert-Butoxycarbonyl)-4-[4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-oxo-1-piperazinylmethyl]isonipecotinicAcid REFERENCE EXAMPLE 4-11-[1,4-Bis(tert-butoxycarbonyl)-4-piperidylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone

[0340]4-Benzyloxycarbonyl-1-[1,4-bis(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone(21.7 g) was dissolved in ethanol (200 ml), 10% palladium carbon (3.5 g)was added, and the mixture was vigorously stirred for 1 hour under ahydrogen stream. After the catalyst was removed, the solvent wasdistilled off under reduced pressure. The resulting residue (16.1 g) wasdissolved in dichloromethane (320 ml). After N-ethyldiisopropylamine(8.36 ml) was added, a solution of7-chloro-4H-4-oxobenzopyran-3-sulfonyl chloride (12.3 g) indichloromethane (160 ml) was added in portions under ice-cooling, andthe mixture was stirred at 0° C. for 2 hours. The reaction mixture waswashed with an aqueous sodium bicarbonate solution and an aqueoussaturated sodium chloride solution, dried and concentrated to obtain theresidue, which was purified by silica gel column chromatography (ethylacetate). Sodium borohydrate (1.41 g) was added to a solution of theresulting crystalline powder (16.0 g) in methanol/THF (1:1, 400 ml)under ice-cooling, and the mixture was stirred at 0° C. for 1 hour.Acetic acid (2.13 ml) was added to the reaction mixture, and the mixturewas concentrated. To the residue was added water, the mixture wasextracted with ethyl acetate-THF, washed successively with an aqueoussaturated sodium bicarbonate solution and an aqueous saturated sodiumchloride solution, and dried. The solvent was distilled off to obtainthe residue, which was dissolved in THF (180 ml), triethylamine (10.4ml), followed by a solution of methanesulfonyl chloride (2.88 ml) in THF(20 ml) were added at 0° C., and the mixture was stirred at roomtemperature overnight. During that process, triethylamine (6.9 ml) andmethanesulfonyl chloride (0.96 ml) were further added. Ethyl acetate wasadded to the reaction solution, and the mixture was washed successivelywith water, 10% aqueous citric acid, an aqueous saturated sodiumbicarbonate solution and an aqueous saturated sodium chloride solution,dried, and concentrated. The resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1→1:2) to obtain thecolorless amorphous title compound (14.2 g).

[0341]¹H-NMR (CDCl₃) δ: 1.30-1.60 (2H, m), 1.44 (9H, s), 1.47 (9H, s),1.90-2.10 (2H, m), 2.70-3.00 (2H, m), 3.30-3.80 (6H, m), 3.80-4.05 (2H,m), 3.89 (2H, s), 4.88 (2H, d, J=1.2 Hz), 6.92 (1H, d, J=1.9 Hz), 6.99(1H, dd, J=8.1, 1.9 Hz), 7.13 (1H, d, J=8.1 Hz), 7.27 (1H, s).

REFERENCE EXAMPLE 4-21-(tert-Butoxycarbonyl)-4-[4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-oxo-1-piperazinylmethyl]isonipecotinicAcid

[0342] According to the same manner as that of Reference Example 2-2except that1-[1,4-bis(tert-butoxycarbonyl)-4-piperidylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinonewas used, the colorless crystalline title compound was obtained.

[0343]¹H-NMR (CDCl₃) δ: 1.20-1.50 (2H, m), 1.45 (9H, s), 2.00-2.20 (2H,m), 2.70-3.00 (2H, m), 3.40-3.75 (2H, m), 3.52 (4H, s), 3.85-4.10 (2H,m), 3.93 (2H, s), 4.88 (2H, s), 6.91 (1H, d, J=1.6 Hz), 6.98 (1H, dd,J=8.1, 1.6 Hz), 7.15 (1H, d, J=8.1 Hz), 7.30 (1H, s).

REFERENCE EXAMPLE 51-[4-Amino-1-(4-pyridyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinoneDihydrochloride REFERENCE EXAMPLE 5-11-[4-Benzyloxycarbonylamino-1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone

[0344] Triethylamine (1.67 ml) and diphenylphosphoryl azide (2.59 ml)were added to a solution of1-(tert-butoxycarbonyl)-4-[4-(6-chloro-2-naphthalenesulfonyl)-2-oxo-1-piperazinylmethyl]isonipecotinicacid (5.66 g) in toluene (100 ml), and the mixture was stirred at roomtemperature for 1 hour, and at 100° C. for 30 minutes. Benzyl alcohol(1.57 ml) was added to the reaction mixture, and the mixture was furtherstirred at 100° C. overnight. The reaction mixture was concentrated, andthe resulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=1:1) to obtain the amorphous title compound (7.42g).

[0345]¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 1.35-2.00 (4H, m), 2.77-2.95 (2H,m), 3.05-3.35 (4H, m), 3.55-3.90 (6H, m), 4.47 (1H, s), 5.02 (2H, s),7.30-7.45 (5H, m), 7.60 (1H, dd, J=8.8, 1.8 Hz), 7.75 (1H, dd, J=8.8,1.8 Hz), 7.88-7.98 (3H, m), 8.32 (1H, s).

REFERENCE EXAMPLE 5-21-[4-Benzyloxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone

[0346] A 4N hydrochloric acid solution in ethyl acetate (50 ml) andethanol (10 ml) was added to1-[4-benzyloxycarbonylamino-1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone(7.42 g), and the mixture was stirred at room temperature for 1 hour.The reaction mixture was concentrated under reduced pressure,4-chloropyridine hydrochloride (1.80 g), triethylamine(6.97 ml) andethanol (100 ml) were added to the residue, and the mixture was heatedat 150° C. for 5 hours in a sealed tube. After cooling, the reactionmixture was diluted with ethyl acetate, and washed with water. The ethylacetate layer was dried with magnesium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gelchromatography (ethyl acetate-ethyl acetate/methanol=8/1) to obtain thetitle compound (3.58 g, 55%) as powders.

[0347]¹H-NMR (CDCl₃) δ: 1.55-1.80 (2H, m), 1.80-2.05 (2H, m), 2.85-3.05(2H, m), 3.15-3.33 (4H, m), 3.45-3.62 (2H, m), 3.66 (2H, s), 3.77 (2H,s), 4.60 (1H, s), 5.04 (2H, s), 6.60 (2H, d, J=6.3 Hz), 7.30-7.45 (5H,m), 7.61 (1H, dd, J=8.9, 1.9 Hz), 7.76 (1H, dd, J=8.7, 1.7 Hz),7.88-7.98 (3H, m), 8.25 (2H, d, J=6.3 Hz), 8.34 (1H, s).

REFERENCE EXAMPLE 5-31-[4-Amino-1-(4-pyridyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinoneDihydrochloride

[0348] Iodotrimethylsilane (2.51 ml) was added to a solution of1-[4-benzyloxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone(4.58 g) in dichloromethane (50 ml), and the mixture was stirred at roomtemperature for 4 hours. Methanol (10 ml) and 4N hydrochloric acidsolution in ethyl acetate (8 ml) were added thereto. Methanol was addedto obtain a solution, followed by concentration under reduced pressure.Dilute hydrochloric acid was added to the residue, and the mixture waswashed with ether. The aqueous layer was made basic with 6N sodiumhydroxide, followed by extraction with ethyl acetate. The organic layerwas washed successively with an aqueous sodium bicarbonate solution andan aqueous saturated sodium chloride solution, dried, and concentrated.Dilute hydrochloric solution was added to the residue, which waspurified by CHP20 column chromatography (water:acetonitrile:1Nhydrochloric acid=100:0:1→80:20:1) to obtain the colorless amorphoustitle compound (3.66 g).

[0349]¹H-NMR (DMSO-d₆) δ: 1.86 (4H, br), 3.38 (2H, m), 3.46-3.64 (4H,m), 3.68 (2H, s), 3.70-4.00 (4H, m), 7.19 (2H, d, J=7.4 Hz), 7.76 (1H,dd, J=8.8, 2.2 Hz), 7.92 (1H, dd, J=8.6, 1.8 Hz), 8.18-8.55 (8H, m),8.63 (1H, s).

REFERENCE EXAMPLE 64-[[4-(Benzyloxycarbonyl)-2-oxo-1-piperazinyl]methyl]-1-(tert-butoxycarbonyl)-4-piperidinecarboxylicAcid

[0350] Trifluoroacetic acid (100 ml) was added to a solution of4-benzyloxycarbonyl-1-[1,4-bis(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone(38.8 g) obtained in Reference Example 1 in toluene (100 ml), themixture was stirred at room temperature for 1 hour, and concentratedunder reduced pressure. Then, di-tert-butyl dicarbonate (17.6 ml) wasadded to a mixture of the residue, sodium carbonate (38.7 g), water (300ml) and ethyl acetate (300 ml) at room temperature while stirring, andthe mixture was stirred at room temperature for 1 hour. The reactionmixture was separated into layers, the aqueous layer was adjusted to pH3 with 1N hydrochloric acid, and extracted with ethyl acetate. The ethylacetate layer was dried with magnesium sulfate, and concentrated underreduced pressure, and the residue was purified by silica gelchromatography (ethyl acetate:methanol=10/1) to obtain the titlecompound (29 g) as yellow powders.

[0351]¹H-NMR (CDCl₃+D₂O): δ 1.30-1.58 (2H, m), 1.44 (9H, s), 2.00-2.20(2H, m), 2.74-2.98 (2H, m), 3.36-3.74 (6H, m), (5H, m 0.86-4.06 (2H, m),4.16 (2H, s), 5.15 (2H, s), 7.30-7.40 (5H, m).

REFERENCE EXAMPLE 7 Benzyl4-[[1-(tert-Butoxycarbonyl)-4-[(ethoxycarbonyl)amino]-4-piperidinyl]methyl]-3-oxo-1-piperazinecarboxylate

[0352] Diphenylphosphoryl azide (15.8 ml) was added to a mixture of4-[[4-(benzyloxycarbonyl)-2-oxo-1-piperazinyl]methyl]-1-(tert-butoxycarbonyl)-4-piperidinecarboxylicacid (29 g) obtained in Reference Example 6, triethylamine (10.2 ml) andtoluene (290 ml) at 0° C. under stirring, and the mixture was stirred atroom temperature for 1 hour, and at 100° C. for 2 hours. Ethanol (290ml) was added, and the mixture was heated under reflux for 12 hours, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (hexane/ethyl acetate=1/3-ethylacetate/methanol=10/1) to obtain the title compound (26 g, 82%) as paleyellow powders.

[0353]¹H-NMR (CDCl₃): δ 1.23 (3H, t, J=7.0 Hz), 1.44 (9H, s), 1.50-1.73(2H, m), 1.82-2.05 (2H, m), 2.90-3.10 (2H, m), 3.40-3.53 (2H, m),3.60-3.92 (6H, m), 4.08 (2H, q, J=7.0 Hz), 4.16 (2H, s), 4.59 (1H, s),5.16 (2H, s), 7.30-7.42 (5H, m).

REFERENCE EXAMPLE 8 Benzyl4-[[4-[(ethoxycarbonyl)amino]-4-piperidinyl]methyl]-3-oxo-1-piperazinecarboxylateTrifluoroacetate

[0354] Trifluoroacetic acid (78 ml) was added to a solution of benzyl4-[[1-(tert-butoxycarbonyl)-4-[(ethoxycarbonyl)amino]-4-piperidinyl]methyl]-3-oxo-1-piperazinecarboxylate(26 g) obtained in Reference Example 7 in toluene (78 ml) at roomtemperature while stirring, and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated underreduced pressure, and the residue was crystallized from ethylacetate/diethyl ether=5/1) to obtain the title compound (16 g, 60%) ascolorless crystals.

[0355]¹H-NMR (DMSO-d₆+D₂O): δ 1.17 (3H, t, J=7.0 Hz), 1.52-1.78 (2H, m),2.04-2.24 (2H, m), 2.76-2.98 (2H, m), 3.04-3.24 (2H, m), 3.32-3.48 (2H,m), 3.50-3.68 (4H, m), 3.90-4.10 (4H, m), 5.11 (2H, s), 7.30-7.50 (5H,m).

REFERENCE EXAMPLE 9 Benzyl4-[[4-[(ethoxycarbonyl)amino]-1-(4-pyridinyl)-4-piperidinyl]methyl]-3-oxo-1-piperidinecarboxylate

[0356] A mixture of benzyl4-[[4-[(ethoxycarbonyl)amino]-4-piperidinyl]methyl]-3-oxo-1-piperazinecarboxylatetrifluoroacetate (15.9 g) obtained in Reference Example 8,4-chloropyridine hydrochloride (5.39 g), triethylamine (41.7 ml) andethanol (159 ml) was heated at 150° C. for 5 hours in a sealed tube.After cooling, the reaction mixture was diluted with ethyl acetate, andwashed with water. The ethyl acetate layer was dried with magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel chromatography (ethyl acetate-ethylacetate/methanol=8/1) to obtain the title compound (9.3 g, 63%) asyellow powders.

[0357] IR (KBr) 2930, 1713, 1599, 1260, 1238 cm⁻¹. ¹H-NMR (CDCl₃): δ1.24 (3H, t, J=7.2 Hz), 1.70-1.90 (2H, m), 2.02-2.18 (2H, m), 2.98-3.16(2H, m), 3.42-3.74 (6H, m), 3.79 (2H, s), 4.09 (2H, q, J=7.2 Hz), 4.17(2H, s), 4.67 (1H, s), 5.16 (2H, s), 6.65 (2H, d, J=6.4 Hz), 7.30-7.55(5H, m), 8.26 (2H, d, J=6.4 Hz).

REFERENCE EXAMPLE 104-Benzyloxycarbonyl-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone

[0358] 4-Chloro-2-methylpyridine hydrochloride (941 mg), triethylamine(1.93 g) and ethanol (50 ml) were added to4-benzyloxycarbonyl-1-[(4-ethoxycarbonylamino-4-piperidinyl)methyl]-2-piperazinone(2.0 g), and the mixture was reacted at 150° C. for 10 hours in a sealedtube. The reaction mixture was concentrated, a 10% aqueous sodiumcarbonate solution was added to the residue, and the mixture wasextracted with dichloromethane, dried, and concentrated. The resultingresidue was purified by column chromatography (dichloromethane:10%aqueous ammonia-containing methanol=20:1) to obtain the colorlessamorphous title compound (1.31 g).

[0359]¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=7.0 Hz), 1.79 (2H, m), 2.07 (2H,m), 2.44 (3H, s), 3.06 (2H, m), 3.40-3.75 (6H, m), 3.78 (2H, s), 4.08(2H, q, J=7.0 Hz), 4.17 (2H, s), 4.59 (1H, s), 5.16 (2H, s), 6.45-6.55(2H, m), 7.37 (5H, s), 8.16 (1H, d, J=6.0 Hz).

REFERENCE EXAMPLE 111-{[4-Ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinoneHydrochloride

[0360] A 4N hydrochloric acid solution in ethyl acetate (0.7 ml) and 10%palladium carbon (500 mg) were added to a solution of4-benzyloxycarbonyl-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidiny]methyl}-2-piperazinone(1.3 g) in ethanol (50 ml), and the mixture was stirred at roomtemperature for 15 hours under a nitrogen atmosphere. After the catalystwas removed, the solvent was distilled off to obtain the colorlessamorphous title compound (1.15 g).

[0361]¹H-NMR (CD₃OD) δ: 1.25 (3H, t, J=7.0 Hz), 1.73 (2H, m), 2.33 (2H,m), 2.51 (3H, s), 3.25-3.45 (4H, m), 3.67 (2H, m), 3.73 (2H, s), 3.77(2H, s), 3.95-4.15 (4H, m), 7.00-7.10 (2H, m), 7.98 (1H, d, J=8.0 Hz).

REFERENCE EXAMPLE 121-{[1-(tert-Butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidinyl]methyl}-2-piperazinone

[0362] 10% Palladium carbon (600 mg) was added to a solution of4-benzyloxycarbonyl-1-{[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidinyl]methyl}-2-piperazinone(1.79 g) in ethanol (50 ml), and the mixture was stirred at roomtemperature for 15 hours under a nitrogen atmosphere. After the catalystwas filtered, the solvent was distilled off to obtain the colorlessamorphous title compound (1.46 g).

[0363]¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.0 Hz), 1.44 (9H, s), 1.54 (2H,m), 2.15 (2H, m), 3.00 (2H, m), 3.40-4.20 (12H, m), 5.60 (1H, brs), 9.93(1H, s).

REFERENCE EXAMPLE 131-{[1-(Tert-butoxycarbonyl-4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzenesulfonyl)-2-piperazinone

[0364] Triethylamine (735 mg) was added to a solution of1-{[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidinyl]methyl}-2-piperazinone(1.4 g) in dichloromethane (80 ml), and 4-vinylbenzenesulfonyl chloride(885 mg) was added at 0° C., and the mixture was stirred at roomtemperature for 1 hour. An aqueous sodium carbonate solution was addedto the reaction solution, and the mixture was extracted withdichloromethane, dried, concentrated, and purified by silica gel columnchromatography (hexane:ethyl acetate=1:2) to obtain the colorlessamorphous title compound (1.50 g).

[0365]¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=7.0 Hz), 1.43 (9H, s), 1.56 (2H,m), 1.84 (2H, m), 2.95 (2H, m), 3.30 (2H, m), 3.51 (2H, m), 3.60-3.90(6H, m), 4.06 (2H, q, J=7.0 Hz), 4.49 (1H, brs), 5.48 (1H, d, J=ll.OHz),5.92 (1H, d, J=17.6 Hz), 6.77 (1H, dd, J=11.0, 17.6 Hz), 7.58 (2H, d,J=8.4 Hz), 7.75 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 141-{[4-Eethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzenesulfonyl)-2-piperazinoneHydrochloride

[0366] A 4N hydrochloric acid solution in ethyl acetate (20 ml) wasadded to1-{[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzenesulfonyl)-2-piperazinone(2.0 g), and the mixture was stirred at room temperature for 30 minutes.The solvent was distilled off to obtain the colorless amorphous titlecompound (1.45 g).

EXAMPLE 14-(6-Chloronaphthalene-2-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinoneEXAMPLE 1-11-[1-(tert-Butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone

[0367] Triethylamine (0.836 ml) and diphenylphosphoryl azide (1.29 ml)were added to a solution of1-(tert-butoxycarbonyl)-4-[4-(6-chloro-2-naphthalenesulfonyl)-2-oxo-1-piperazinylmethyl]isonicopetinicacid (2.83 g) in toluene(50 ml), and the mixture was stirred at 100° C.for 30 minutes. Ethanol (30 ml) was added to the reaction mixture, andthe mixture was further stirred at 70° C. overnight. The reactionsolution was concentrated under reduced pressure, ethyl acetate wasadded thereto, and the mixture was washed successively with an aqueoussaturated sodium bicarbonate solution and an aqueous saturated sodiumchloride solution, dried and concentrated to obtain the amorphous titlecompound (3.90 g).

[0368]¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 1.43 (9H, s), 1.40-2.00(4H, m), 2.80-3.00 (2H, m), 3.30-3.42 (2H, m), 3.48-3.60 (2H, m), 3.67(2H, s), 3.80 (2H, s), 3.65-3.90 (2H, m), 4.04 (2H, q, J=7.1 Hz), 4.42(1H, brs), 7.61 (1H, dd, J=8.9, 1.9 Hz), 7.80 (1H, dd, J=8.6, 1.6 Hz),7.92-8.00 (3H, m), 8.36 (1H, s).

EXAMPLE 1-24-(6-Chloronaphthalene-2-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone

[0369] A 4N hydrochloric acid solution in ethyl acetate (30 ml) andethanol (6 ml) were added to1-[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone(5.21 g), and the mixture was stirred at room temperature for 1 hour.The reaction mixture was concentrated, the precipitated crystals werefiltered off, washed with ethyl acetate-ethanol, and dried to obtain1-[4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinonehydrochloride (3.71 g). A solution of1-[4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinonehydrochloride (3.40 g), 4-chloropyridine hydrochloride (1.12 g) andtriethylamine (3.48 ml) in ethanol (100 ml) was reacted at 150° C. for 9hours in a sealed tube. The reaction mixture was concentrated underreduced pressure, ethyl acetate was added thereto, and the mixture waswashed with a 5% aqueous sodium carbonate solution and water, andconcentrated. The resulting residue was purified by silica gel columnchromatography (ethyl acetate:10% aqueous ammonia-containingmethanol=95:5→80:20), and the precipitated crystals were washed withethanol-ether to obtain the colorless crystalline title compound (1.52g).

[0370]¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 1.60-2.05 (4H, m),2.86-3.05 (2H, m), 3.33-3.42 (2H, m), 3.46-3.65 (4H, m), 3.71 (2H, s),3.81 (2H, s), 4.05 (2H, q, J=7.1 Hz), 4.55 (1H, brs), 6.62 (2H, d, J=6.5Hz), 7.62 (1H, dd, J=8.9, 1.9 Hz), 7.81 (1H, dd, J=8.6, 1.8 Hz),7.90-8.00 (3H, m), 8.26 (2H, d, J=6.5 Hz), 8.36 (1H, s).

EXAMPLE 24-(6-Chloronaphthalene-2-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinoneHydrochloride

[0371] Ethanol (20 ml) and a 4N hydrochloric acid solution in ethylacetate (2 ml) were added to4-(6-chloronaphthalene-2-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone(1.3 g) obtained in Example 1, to dissolve the material. Subsequently,ethyl acetate (200 ml) and ether (200 ml) were added, the resultingprecipitates were filtered off, and washed with ether to obtain thecolorless amorphous title compound (1.26 g).

[0372]¹H-NMR (DMSO-d₆) δ: 1.15 (3H, t, J=7.0 Hz), 1.47 (2H, m), 2.11(2H, m), 3.05-3.55 (8H, m), 3.63 (2H, s), 3.90-4.05 (4H, m), 7.15 (2H,d, J=6.6 Hz), 7.17 (1H, brs), 7.74 (1H, dd, J=2.2, 8.8 Hz), 7.88 (1H,dd, J=1.8, 8.8 Hz), 8.15-8.33 (5H, m), 8.59 (1H, s).

EXAMPLE 34-(6-Chloronaphthalene-2-sulfonyl)-1-[4-methoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone

[0373] According to the same manner as that of Example 1,1-(tert-butoxycarbonyl)-4-[4-(6-chloro-2-naphthalenesulfonyl)-2-oxo-1-piperazinylmethyl]isonipecotinicacid and methanol were used to obtain the colorless crystalline titlecompound.

[0374]¹H-NMR (CDCl₃) δ: 1.60-2.10 (4H, m), 2.87-3.06 (2H, m), 3.33-3.42(2H, m), 3.50-3.60 (4H, m), 3.63 (3H, s), 3.71 (2H, s), 3.82 (2H, s),4.64 (1H, brs), 6.61 (2H, d, J=6.5 Hz), 7.62 (1H, dd, J=8.9, 1.9 Hz),7.80 (1H, dd, J=8.6, 1.8 Hz), 7.92-8.00 (3H, m), 8.25 (2H, d, J=6.5 Hz),8.36 (1H, s).

EXAMPLE 44-(6-Chloromaphtalene-2-sulfonyl)-1-[4-propoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-2-piperadinonEXAMPLE 4-1 O-Propoxycarbonyl-4-nitrophenol

[0375] A solution of propyl chloroformate (613 mg) in THF (3 ml) wasadded to a solution of 4-nitrophenol (693 mg) and triethylamine (0.836ml) in THF (10 ml) at 0° C. After stirred at room temperature for 30minutes, water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with a 10% aqueous sodiumcarbonate solution, an aqueous saturated sodium bicarbonate solution andan aqueous saturated sodium chloride solution, dried, and concentratedto obtain the title compound (1.11 g) as a pale yellow solid.

[0376]¹H-NMR (CDCl₃) δ: 1.03 (3H, t, J=7.4 Hz), 1.70-1.90 (2H, m), 4.26(2H, t, J=6.7 Hz), 7.39 (2H, d, J=9.3 Hz), 8.29 (2H, d, J=9.3 Hz).

EXAMPLE 4-24-(6-Chloronaphthalene-2-sulfonyl)-1-[4-propoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone

[0377] A solution of1-[4-amino-1-(4-pyridyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinonedihydrochloride (235 mg), O-propoxycarbonyl-4-nitrophenol (270 mg) andN-ethyldiisopropylamine (0.348 ml) in DMF (5 ml) was stirred at 80° C.overnight. To the reaction solution was added ethyl acetate, the mixturewas washed successively with a 10% aqueous sodium carbonate solution, anaqueous saturated sodium bicarbonate solution and an aqueous saturatedsodium chloride solution, dried, and concentrated. The residue waspurified by silica gel column chromatography (ethyl acetate:10% aqueousammonia-containing methanol=90:10→80:20), and crystallized from a mixedsolution of acetone and ethyl acetate to obtain the pale browncrystalline title compound (114 mg).

[0378]¹H-NMR (CDCl₃) δ: 0.92 (3H, t, J=7.5 Hz), 1.50-2.05 (6H, m),2.88-3.05 (2H, m), 3.32-3.42 (2H, m), 3.48-3.64 (4H, m), 3.71 (2H, s),3.81 (2H, s), 3.96 (2H, q, J=6.8 Hz), 4.54 (1H, brs), 6.61 (2H, d, J=6.6Hz), 7.62 (1H, dd, J=9.0, 2.0 Hz), 7.80 (1H, dd, J=8.4, 1.8 Hz),7.90-8.00 (3H, m), 8.25 (2H, d, J=6.8 Hz), 8.35 (1H, s).

EXAMPLE 54-(7-Chloro-2H-benzopyran-3-sulfonyl)-1-[4-methoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone

[0379] According to the same manner as that of Example 1,1-(tert-butoxycarbonyl)-4-[4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-oxo-1-piperazinylmethyl]isonipecotinicacid and methanol were used to obtain the colorless crystalline titlecompound

[0380]¹H-NMR (CDCl₃) δ: 1.68-1.88 (2H, m), 2.00-2.20 (2H, m), 2.94-3.13(2H, m), 3.50-3.68 (6H, m), 3.63 (3H, s), 3.79 (2H, s), 3.93 (2H, s),4.80 (1H, brs), 4.89 (2H, s), 6.64 (2H, d, J=6.6 Hz), 6.94 (1H, d, J=1.9Hz), 7.02 (1H, dd, J=8.0, 1.9 Hz), 7.15 (1H, d, J=8.0 Hz), 7.29 (1H, s),8.27 (2H, d, J=6.6 Hz).

EXAMPLE 64-(7-Chloro-2H-benzopyran-3-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone

[0381] According to the same manner as that of Example 1,1-(tert-butoxycarbonyl)-4-[4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-oxo-1-piperazinylmethyl]isonipecotinicacid and ethanol were used to obtain the colorless crystalline titlecompound.

[0382]¹H-NMR (CDCl₃) δ: 1.21 (3H, t, J=7.2 Hz), 1.70-1.88 (2H, m),2.00-2.20 (2H, m), 2.95-3.13 (2H, m), 3.50-3.70 (6H, m), 3.80 (2H, s),3.94 (2H, s), 4.06 (2H, q, J=7.2 Hz), 4.79 (1H, brs), 4.89 (2H, s), 6.64(2H, d, J=6.6 Hz), 6.94 (1H, d, J=1.9 Hz), 7.02 (1H, dd, J=8.1, 1.9 Hz),7.15 (1H, d, J=8.1 Hz), 7.30 (1H, s), 8.27 (2H, d, J=6.6 Hz).

EXAMPLE 74-(7-Chloro-2H-benzopyran-3-sulfonyl)-1-[4-propoxycarbonylamine-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone

[0383] According to the same manner as that of Example 1,1-(tert-butoxycarbonyl)-4-[4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-oxo-1-piperazinylmethyl]isonicopetinicacid and propanol were used to obtain the colorless amorphous titlecompound.

[0384]¹H-NMR (CDCl₃) δ: 0.91 (3H, t, J=7.5 Hz), 1.50-1.90 (4H, m),2.00-2.20 (2H, m), 2.95-3.15 (2H, m), 3.50-3.70 (6H, m), 3.80 (2H, s),3.94 (2H, s), 3.97 (2H, q, J=7.0 Hz), 4.74 (1H, brs), 4.89 (2H, s), 6.64(2H, d, J=6.4 Hz), 6.94 (1H, d, J=1.8 Hz), 7.02 (1H, dd, J=8.0, 1.9 Hz),7.15 (1H, d, J=8.0 Hz), 7.30 (1H, s), 8.27 (2H, d, J=6.4 Hz).

EXAMPLE 81-[4-Methoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-4-vinylbenzensulfonyl-2-piperazinone

[0385] According to the same manner as that of Example 1,1-(tert-butoxycarbonyl)-4-[2-oxo-4-(4-vinylbenzenesulfonyl)-1-piperazinylmethyl]isonicopetinicacid and methanol were used to obtain the colorless crystalline titlecompound.

[0386]¹H-NMR (CDCl₃) δ: 1.65-1.85 (2H, m), 1.95-2.12 (2H, m), 2.94-3.13(2H, m), 3.25-3.35 (2H, m), 3.48-3.65 (4H, m), 3.64 (3H, s), 3.72 (2H,s), 3.75 (2H, s), 4.66 (1H, brs), 5.49 (1H, d, J=11.0 Hz), 5.91 (1H, d,J=17.5 Hz), 6.63 (2H, d, J=6.4 Hz), 6.77 (1H, dd, J=17.5, 11.0 Hz), 7.58(2H, d, J=8.4 Hz), 7.76 (2H, d, J=8.4 Hz), 8.26 (2H, d, J=6.4 Hz).

EXAMPLE 91-[4-Ethoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-4-vinylbenzensulfonyl-2-piperazinone

[0387] According to the same manner as that of Example 1,1-(tert-butoxycarbonyl)-4-[2-oxo-4-(4-vinylbenzenesulfonyl)-1-piperazinylmethyl]isonipecotinicacid and ethanol were used to obtain the colorless crystalline titlecompound.

[0388]¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.1 Hz), 1.65-1.85 (2H, m),1.95-2.10 (2H, m), 2.95-3.12 (2H, m), 3.27-3.36 (2H, m), 3.50-3.68 (4H,m), 3.73 (2H, s), 3.75 (2H, s), 4.07 (2H, q, J=7.1 Hz), 4.61 (1H, brs),5.49 (1H, d, J=10.9 Hz), 5.92 (1H, d, J=17.6 Hz), 6.64 (2H, d, J=6.6Hz), 6.77 (1H, dd, J=17.6, 10.9 Hz), 7.59 (2H, d, J=8.4 Hz), 7.76 (2H,d, J=8.4 Hz), 8.26 (2H, d, J=6.6 Hz).

EXAMPLE 101-[4-Propoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-4-vinylbenzensulfonyl-2-piperazinone

[0389] According to the same manner as that of Example 1,1-(tert-butoxycarbonyl)-4-[2-oxo-4-(4-vinylbenzenesulfonyl)-1-piperazinylmethyl]isonipecotinicacid and propanol were used to obtain the pale yellow amorphous titlecompound.

[0390]¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.4 Hz), 1.55-1.90 (4H, m),2.00-2.20 (2H, m), 3.10-3.37 (4H, m), 3.50-3.80 (8H, m), 3.98 (2H, q,J=6.8 Hz), 4.74 (1H, brs), 5.49 (1H, d, J=10.9 Hz), 5.92 (1H, d, J=17.7Hz), 6.68-6.86 (3H, m), 7.59 (2H, d, J=8.4 Hz), 7.75 (2H, d, J=8.4 Hz),8.19 (2H, d, J=6.6 Hz).

EXAMPLE 114-(6-Chloronaphthalene-2-sulfonyl)-1-[4-(2-methoxyethoxycarbonylamino)-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinoneEXAMPLE 11-1 2-Methoxyethyl-4-nitrophenyl Carbonate

[0391] A solution of 4-nitrophenyl chloroformate (1.01 g) in THF (3 ml)was added to a solution of 2-methoxyethanol (381 mg) and triethylamine(0.836 ml) in THF (10 ml) at 0° C. After stirred at 0° C. for 5 hours,water was added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with a 10% aqueous sodium carbonate solution,an aqueous saturated sodium bicarbonate solution and an aqueoussaturated sodium chloride solution, dried, and concentrated to obtainthe title compound (1.11 g) as a pale yellow solid.

[0392]¹H-NMR (CDCl₃) δ: 3.45 (3H, s), 3.68-3.75 (2H, m), 3.42-3.48 (2H,m), 7.40 (2H, d, J=9.3 Hz), 8.29 (2H, d, J=9.3 Hz).

EXAMPLE 11-24-(6-Chloronaphthalene-2-sulphonyl)-1-[4-(2-methoxyethoxycarbonylamino)-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone

[0393] A solution of1-[4-amino-1-(4-pyridyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone(206 mg), 2-methoxyethyl-4-nitrophenyl carbonate (386 mg) andN-ethyldiisopropylamine (0.278 ml) in DMF (5 ml) was stirred at 60° C.overnight. The reaction mixture was concentrated under reduced pressure,ethyl acetate was added, the mixture was washed successively with a 10%aqueous sodium carbonate solution, an aqueous saturated sodiumbicarbonate solution and an aqueous saturated sodium chloride solution,dried, and concentrated. The residue was purified by silica gel columnchromatography (ethyl acetate:10% aqueous ammonia-methanol=90:10→80:20),and crystallized from a mixed solution of acetone and ethyl acetate toobtain the colorless crystalline title compound (145 mg).

[0394]¹H-NMR (CDCl₃) δ: 1.60-2.00 (4H, m), 2.85-3.05 (2H, m), 3.34-3.45(2H, m), 3.40 (3H, s), 3.46-3.62 (6H, m), 3.70 (2H, s), 3.82 (2H, s),4.15-4.24 (2H, m), 4.63 (1H, brs), 6.61 (2H, d, J=6.4 Hz), 7.62 (1H, dd,J=8.8, 2.0 Hz), 7.81 (1H, dd, J=8.6, 1.6 Hz), 7.92-8.00 (3H, m), 8.26(2H, d, J=6.4 Hz), 8.37 (1H, s).

EXAMPLE 124-(6-Chloronaphthalene-2-sulfonyl)-1-[4-(2-fluoroethoxycarbonylamino)-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone

[0395] According to the same manner as that of Example 11,2-fluoroethanol was used in place of 2-methoxyethanol, to obtain thepale brown crystalline title compound.

[0396]¹H-NMR (CDCl₃) δ: 1.60-1.80 (2H, m), 1.90-2.05 (2H, m), 2.87-3.05(2H, m), 3.32-3.43 (2H, m), 3.45-3.62 (4H, m), 3.70 (2H, s), 3.82 (2H,s), 4.17-4.38 (2H, m), 4.41-4.73 (3H,m), 6.62 (2H, d, J=6.6 Hz), 7.62(1H, dd, J=8.9, 1.9 Hz), 7.81 (1H, dd, J=8.8, 1.8 Hz), 7.90-8.00 (3H,m), 8.26 (2H, d, J=6.6 Hz), 8.36 (1H, s).

EXAMPLE 13 Ethyl2-[4-[4-(6-chloro-2-naphthalensulfonyl)-2-oxo-1-piperazinylmethyl]-1-(4-pyridyl)-4-piperidylaminocarbonyloxy]acetate

[0397] According to the same manner as that of Example 11, ethylglycolate was used in place of 2-methoxyethanol, to obtain the colorlesscrystalline title compound.

[0398]¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.2 Hz), 1.60-2.00 (4H, m),2.85-3.05 (2H, m), 3.37-3.73 (6H, m), 3.69 (2H, s), 3.84 (2H, s), 4.21(2H, q, J=7.2 Hz), 4.52 (2H, s), 4.91 (1H, brs), 6.61 (2H, d, J=6.6 Hz),7.62 (1H, dd, J=9.0, 1.8 Hz), 7.80 (1H, dd, J=8.8, 1.8 Hz), 7.90-8.00(3H, m), 8.25 (2H, d, J=6.6 Hz), 8.37 (1H, s).

EXAMPLE 144-(6-Chloronaphthalene-2-sulfonyl)-1-[4-isopropoxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone

[0399] According to the same manner as that of Example 11, isopropanolwas used in place of 2-methoxyethanol, to obtain the colorlesscrystalline title compound.

[0400]¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.4 Hz), 1.60-2.05 (4H, m),2.85-3.05 (2H, m), 3.32-3.44 (2H, m), 3.48-3.53 (4H, m), 3.71 (2H, s),3.82 (2H, s), 4.42 (1H, brs), 4.75-4.92 (1H, m), 6.61 (2H, d, J=5.7 Hz),7.62 (1H, d, J=9.0 Hz), 7.80 (1H, dd, J=8.8, 1.8 Hz), 7.90-8.00 (3H, m),8.26 (2H, d, J=5.7 Hz), 8.36 (1H, s).

EXAMPLE 152-[4-[4-(6-Chloro-2-naphthalensulfonyl)-2-oxo-1-piperazinylmethyl]-1-(4-pyridyl)-4-peperidylaminocarbonyloxy]aceticAcid

[0401] A mixture of ethyl2-[4-[4-(6-chloro-2-naphthalenesulfonyl)-2-oxo-1-piperazinylmethyl]-1-(4-pyridyl)-4-piperidylaminocarbonyloxy]acetate(130 mg) obtained in Example 13, 1N sodium hydroxide (0.4 ml), methanol(10 ml) and dichloromethane (5 ml) was stirred at room temperatureovernight. After neutralized with 1N hydrochloric acid, the reactionmixture was concentrated under reduced pressure, and the resultingresidue was purified by CHP20 column chromatography(water:acetonitrile=10:0→6:4). 1N hydrochloric acid (0.3 ml) was addedto the desired fraction, and the fraction was concentrated under reducedpressure to obtain the colorless amorphous title compound (78 mg).

[0402]¹H-NMR (DMSO-d₆) δ: 1.35-1.62 (2H, m), 2.00-2.18 (2H, m),3.10-3.70 (8H, m), 3.64 (2H, s), 3.90-4.08 (2H, m), 4.48 (2H, s), 7.17(2H, d, J=7.2 Hz), 7.55 (1H, brs), 7.75 (1H, dd, J=8.8, 2.0 Hz), 7.89(1H, dd, J=8.6, 1.6 Hz), 8.14-8.35 (5H, m), 8.60 (1H, s).

EXAMPLE 164-(7-Chloro-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)-4-[2-(1-pyrrolidinyl)ethoxycarbonylamino]-4-piperidinylmethyl]-2-piperazinoneDihydrochloride

[0403] A 4N hydrochloric acid solution in ethyl acetate (10 ml) andethanol (2 ml) were added to1-[1-(tert-butoxycarbonyl)-4-[2-(1-pyrrolidinyl)ethoxycarbonylamino]-4-piperidylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-piperazinone(460 mg) obtained in the same method as that in Example 7-1 using1-(tert-butoxycarbonyl)-4-[4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-oxo-1-piperazinylmethyl]isonipecotinicacid and 2-hydroxypyrrolidine, and the mixture was stirred at roomtemperature for 1 hour. The reaction solution was concentrated underreduced pressure, 4-chloropyridine hydrochloride (112 mg),N-ethyldiisopropylamine (0.587 ml), tetrabutylammonium bromide (22 mg),and 2-methoxyethanol (10 ml) were added to the resulting residue, toreact at 120° C. for 2 days. Ethyl acetate was added to the reactionsolution, and the mixture was washed with 5% aqueous sodium carbonateand an aqueous saturated sodium chloride solution, dried, andconcentrated. The resulting residue was purified by basic silica gelcolumn chromatography (ethyl acetate:ethanol=10:0→9:1). 1N Hydrochloricacid was added to the desired fraction, and the fraction was purifiedagain by CHP20 column chromatography (water:acetonitrile:1N hydrochloricacid=100:0:0.5→70:30:0.5) to obtain the pale yellow amorphous titlecompound (167 mg).

[0404]¹H-NMR (DMSO-d₆) δ 1.45-1.75 (2H, m), 1.75-2.10 (4H, m), 2.10-2.30(2H, m), 2.90-3.70 (14H, m), 3.80 (2H, s), 3.97-4.14 (2H, m), 4.22-4.34(2H, m), 5.01 (2H, s), 7.08 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=8.1, 1.8Hz), 7.20 (2H, d, J=7.4 Hz), 7.43 (1H, brs), 7.49 (1H, d, J=8.1 Hz),7.50 (1H, s), 8.16-8.27 (2H, m).

EXAMPLE 17 Ethyl4-[[4-[(6-bromo-2-naphthyl)sulfonyl]-2-oxo-1-piperazinyl]methyl]-1-(4-pyridinyl)-4-piperidinylcarbamate

[0405] A mixture of benzyl4-[[4-[(ethoxycarbonyl)amino]-1-(4-pyridinyl)-4-piperidinyl]methyl]-3-oxo-1-piperidinecarboxylate(3.27 g) obtained in Reference Example 9, 4N hydrochloric acid/ethylacetate (1.65 ml), 10% Pd—C (0.33 g) and methanol (65 ml) was stirredfor 1 hour under the hydrogen atmosphere. The catalyst was removed byfiltration, and the filtrate was concentrated under reduced pressure.Then, to a stirring mixture of the resulting oil, sodium carbonate (3.50g), methylene chloride (30 ml) and water (30 ml) was added6-bromonaphthalenesulfonyl chloride (2.42 g) at room temperature, andthe mixture was stirred at room temperature for 2 hours. The reactionmixture was separated into layers, the organic layer was washed with 1Nsodium hydroxide and water, dried with magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (methylene chloride/methanol=10/1-methylenechloride/methanol/25% aqueous ammonia=100/10/1) to obtain the pinkcrystalline title compound (2.4 g, 56%).

[0406]¹H-NMR (CDCl₃): δ 1.22 (3H, t, J =7.0 Hz), 1.57-1.83 (2H, m),1.85-2.06 (2H, m), 2.85-3.07 (2H, m), 3.33-3.43 (2H, m), 3.45-3.65 (4H,m), 3.70 (2H, s), 3.81 (2H, s), 4.05 (2H, q, J =7.0 Hz), 4.56 (1H, s),6.61 (2H, d, J =6.4 Hz), 7.70-7.98 (4H, m), 8.13 (1H, d, J =1.4 Hz),8.25 (2H, d, J=6.4 Hz), 8.35 (1H, s).

EXAMPLE 18 Ethyl4-[[4-[(6-bromo-2-naphthyl)sulfonyl]-2-oxo-1-piperazinyl]methyl]-1-(4-pyridyl)-4-piperidinylcarbamateHydrochloride

[0407] Ethyl4-[[4-[(6-bromo-2-naphthyl)sulfonyl]-2-oxo-1-piperazinyl]methyl]-1-(4-pyridinyl)-4-piperidinylcarbamate(2.0 g) obtained in Example 17 was suspended in ethanol (20 ml), and 4Nhydrochloric acid/ethyl acetate (1.2 ml) was added thereto at roomtemperature, followed by concentration under reduced pressure. Theresidue was dissolved in ethanol (8 ml), and ethyl acetate (50 ml) anddiethyl ether (50 ml) were added. The resulting powders were collectedto obtain the title compound (1.82 g) as colorless powders.

[0408]¹H-NMR (DMSO-d₆+D₂O): δ 1.16 (3H, t, J=7.0 Hz), 1.35-1.58 (2H, m),2.00-2.20 (2H, m), 3.05-4.10 (14H, m), 7.08-7.22 (5H, m), 7.80-7.94 (2H,m), 8.12-8.26 (4H, m), 8.43 (1H, d, J=1.4 Hz), 8.58 (1H, s).

EXAMPLE 19 Ethyl4-[[4-[(7-bromo-2H-chromen-3-yl)sulfonyl]-2-oxo-1-piperazinyl]methyl]-1-(4-pyridinyl)-4-piperidinylcarbamate

[0409] According to the same manner as that of Example 17,7-bromo-3-benzopyranylsulfonyl chloride was used in place of6-bromonaphthalene-2-sulfonyl chloride, to obtain the colorlesscrystalline title compound.

[0410]¹H-NMR (CDCl₃): δ 1.21 (3H, t, J=7.0 Hz), 1.67-1.90 (2H, m),2.00-2.18 (2H, m), 2.93-3.15 (2H, m), 3.47-3.70 (6H, m), 3.79 (2H, s),3.94 (2H, s), 4.06 (2H, q, J=7.0 Hz), 4.79 (1H, s), 4.88 (2H, s), 6.64(2H, d, J=6.6 Hz), 7.02-7.12 (2H, m), 7.18 (1H, dd, J=2.0, 8.2 Hz), 7.28(1H, s), 8.26 (2H, d, J=6.6 Hz).

EXAMPLE 20 Ethyl4-[[4-[(7-bromo-2H-chromen-3-yl)sulfonyl]-2-oso-1-piperazinyl]methyl]-1-(4-pyridinyl)-4-piperidinylcarbamateHydrochloride

[0411] According to the same manner as that of Example 18, the titlecompound as colorless powders was obtained from a free compound.

[0412]¹H-NMR (DMSO-d₆+D₂O): δ 1.17 (3H, t, J=7.0 Hz), 1.40-1.68 (2H, m),2.05-2.30 (2H, m), 3.10-4.20 (14H, m), 4.98 (2H, s), 7.04-7.54 (6H, m),8.20 (2H, d, J=7.0 Hz).

EXAMPLE 214-(6-Chloronaphthalene-2-sulfonyl)-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone

[0413] Triethylamine (253 mg) was added to a solution of1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinonehydrochloride (258 mg) in dichloromethane (15 ml),6-chloronaphthalene-2-sulfonyl chloride (196 mg) was added thereto at 0°C., and the mixture was stirred at room temperature for 1 hour. To thereaction solution was added an aqueous sodium carbonate solution, themixture was extracted with dichloromethane, dried, concentrated, andpurified by column chromatography (dichloromethane:10% aqueousammonia-containing methanol=20:1) to obtain the colorless amorphoustitle compound (255 mg).

[0414]¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.0 Hz), 1.70 (2H, m), 1.96 (2H,m), 2.45 (3H, s), 2.96 (2H, m), 3.37 (2H, m), 3.45-3.60 (4H, m), 3.70(2H, s), 3.81 (2H, s), 4.05 (2H, q, J=7.0 Hz), 4.48 (1H, s), 6.40-6.55(2H, m), 7.62 (1H, dd, J=1.8, 8.8 Hz), 7.80 (1H, dd, J=1.8, 8.8 Hz),7.90-8.00 (3H, m), 8.16 (1H, d, J=6.2 Hz), 8.36 (1H, s). IR (KBr): 1715,1651, 1601, 1539, 1495, 1348, 1262, 1167, 1078 cm⁻¹.

EXAMPLE 224-(6-Chloronaphthalene-2-sulfonyl)-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinoneHydrochloride

[0415]4-(6-Chloronaphthalene-2-sulfonyl)-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone(215 mg) was suspended in ethyl acetate (10 ml), a 4N hydrochloric acidsolution in ethyl acetate (0.3 ml) was added, and the resulting crystalswere filtered off to obtain the title compound (180 mg) as colorlesspowders.

[0416]¹H-NMR (DMSO-d₆) δ: 1.16 (3H, t, J=7.0 Hz), 1.45 (2H, m), 2.11(2H, m), 2.43 (3H, s), 3.08-3.60 (8H, m), 3.63 (2H, s), 3.90-4.05 (4H,m), 7.00-7.10 (2H, m), 7.17 (1H, s), 7.75 (1H, dd, J=2.2, 8.8 Hz), 7.89(1H, dd, J=2.0, 8.8 Hz), 8.09 (1H, m), 8.20 (1H, d, J=8.8 Hz), 8.25-8.35(2H, m), 8.60 (1H, s). IR KBr): 3052, 1713, 1644, 1630, 1537, 1346,1252, 1163 cm⁻¹.

EXAMPLE 234-(7-Bromo-2H-benzopyran-3-sulfonyl)-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinoneHydrochloride

[0417] Triethylamine (253 mg) was added to a solution of1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinonehydrochloride (258 mg) in dichloromethane (15 ml),7-bromo-2H-benzopyran-3-sulfonyl chloride (233 mg) was added at 0° C.,and the mixture was stirred at room temperature for 1 hour. To thereaction solution was added an aqueous sodium carbonate solution, themixture was extracted with dichloromethane, dried, concentrated, andpurified by column chromatography (dichloromethane:10% aqueousammonia-containing methanol=20:1) to obtain colorless amorphous4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone(169 mg).

[0418]¹H-NMR (CDCl₃) δ: 1.20 (3H, t, J=7.0 Hz), 1.77 (2H, m), 2.08 (2H,m), 2.45 (3H, s), 3.04 (2H, m), 3.45-3.70 (6H, m), 3.79 (2H, s), 3.94(2H, s), 4.05 (2H, q, J=7.0 Hz), 4.75 (1H, s), 4.88 (2H, d, J=1.0 Hz),6.40-6.60 (2H, m), 7.08 (1H, d, J=8.0 Hz), 7.11 (1H, d, J=1.8 Hz), 7.18(1H, dd, J=1.8, 8.0 Hz), 7.28 (1H, d, J=1.0 Hz), 8.16 (1H, d, J=5.8 Hz).

[0419] The present product was suspended in ethyl acetate (10 ml), a 4Nhydrochloric acid solution in ethyl acetate (0.3 ml) was added, and theresulting crystals were filtered off to obtain the title compound (137mg) as colorless powders.

[0420]¹H-NMR (DMSO-d₆) δ: 1.17 (3H, t, J=7.0 Hz), 1.51 (2H, m), 2.16(2H, m), 2.44 (3H, s), 3.10-3.65 (8H, m), 3.77 (2H, s), 3.90-4.10 (4H,m), 4.98 (2H, s), 7.00-7.13 (2H, m), 7.18-7.28 (3H, m), 7.41 (1H, d,J=8.0 Hz), 7.48 (1H, s), 8.10 (1H, t, J=6.0 Hz). IR (KBr): 3054, 1713,1644, 1537, 1254, 1159 cm⁻¹.

EXAMPLE 241-{[4-Ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-4-(4-vinylbenzenesulfonyl)-2-piperazinone

[0421] Triethylamine (260 mg) was added to a solution of1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinonehydrochloride (263 mg) in dichloromethane (20 ml),4-vinylbenzenesulfonyl chloride (194 mg) was added at 0° C., and themixture was stirred at room temperature for 1 hour. To the reactionsolution was added an aqueous sodium carbonate solution, the materialwas extracted with dichloromethane, dried, concentrated, purified bycolumn chromatography (dichloromethane:10% aqueous ammonia-containingmethanol=20:1), and crystallized from diisopropyl ether to obtain thecolorless crystalline title compound (157 mg).

[0422]¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.0 Hz), 1.73 (2H, m), 2.00 (2H,m), 2.45 (3H, s), 3.02 (2H, m), 3.30 (2H, m), 3.50-3.70 (4H, m), 3.72(2H, s), 3.75 (2H, s), 4.06 (2H, q, J=7.0 Hz), 4.51 (1H, s), 5.49 (2H,d, J=11.0 Hz), 5.92 (1H, d, J=17.6 Hz), 6.45-6.55 (2H, m), 6.77 (1H, dd,J=11.0, 17.6 Hz), 7.58 (2H, d, J=8.4 Hz), 7.76 (2H, d, J=8.4 Hz), 8.16(1H, d, J=5.8 Hz). IR (KBr): 1713, 1644, 1599, 1352, 1262, 1167 cm⁻¹.

EXAMPLE 251-{[4-Ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-4-(4-vinylbenzenesulfonyl)-2-piperazinoneHydrochloride

[0423]1-{[4-Ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-4-(4-vinylbenzenesulfonyl)-2-piperazinone(86 mg) was suspended in ethyl acetate (10 ml), a 4N hydrochloric acidsolution in ethyl acetate (0.3 ml) was added, and the resulting crystalswere filtered off to obtain the title compound (38 mg) as colorlesspowders.

[0424]¹H-NMR (DMSO-d₆) δ: 1.17 (3H, t, J=7.0 Hz), 1.47 (2H, m), 2.13(2H, m), 2.44 (3H, s), 3.10-3.60 (10H, m), 3.90-4.07 (4H, m), 5.50 (2H,d, J=11.0 Hz), 6.07 (1H, d, J=17.6 Hz), 6.87 (1H, dd, J=11.0, 17.6 Hz),7.00-7.10 (2H, m), 7.19 (1H, s), 7.78 (4H, s), 8.10 (1H, d, J=7.2 Hz).IR (KBr): 3050, 1713, 1644, 1537, 1348, 1254, 1167 cm⁻¹.

EXAMPLE 261-{[4-Ethoxycarbonylamino-1-(2-hydroxymethyl-4-pyridyl)-4-piperidinyl]methyl}-4-(4-vinylbenzensulfonyl)-2-piperazinone

[0425] 4-Chloro-2-(hydroxymethyl)pyridine (118 mg), triethylamine (500mg) and ethanol (15 ml) were added to1-{1-{[4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzenesulfonyl)-2-piperazinonehydrochloride (200 mg), to react at 150° C. for 15 hours in a sealedtube. The reaction solution was concentrated, a 10% aqueous sodiumcarbonate solution was added to the residue, the mixture was extractedwith dichloromethane, dried, and concentrated. The resulting residue wasdried, concentrated, purified by column chromatography(dichloromethane:10% aqueous ammonia-containing methanol=20:1), andcrystallized from ether to obtain the title compound (40 mg) as paleyellow crystals.

[0426]¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.0 Hz), 1.73 (2H, m), 2.02 (2H,m), 3.05 (2H, m), 3.30 (2H, m), 3.45-3.70 (4H, m), 3.72 (2H, s), 3.75(2H, s), 4.07 (2H, q, J=7.0 Hz), 4.57 (1H, brs), 4.63 (2H, s), 5.49 (1H,d, J=11.0 Hz), 5.92 (1H, d, J=17.6 Hz), 6.50-6.60 (2H, m), 6.77 (1H, dd,J=11.0, 17.6 Hz), 7.58 (2H, d, J=8.4 Hz), 7.75 (2H, d, J=8.4 Hz), 8.20(1H, d, J=5.8 Hz).

EXAMPLE 271-{[1-(2-Amino-4-pyridyl)-4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzensulfonyl)-2-piperazinone

[0427] 2-Amino-4-chloropyridine (132 mg), triethylamine (700 mg) andethanol (15 ml) were added to1-{[4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzensulfonyl)-2-piperazinonehydrochloride (250 mg), to react at 155° C. for 20 hours in a sealedtube. The reaction solution was concentrated, a 10% aqueous sodiumcarbonate solution was added to the residue, the material was extractedwith dichloromethane, dried, and concentrated. The resulting residue wasdried, concentrated, purified by column chromatography(dichloromethane:10% aqueous ammonia-containing methanol=20:1), andcrystallized from dichloromethane-hexane to obtain the title compound(58 mg) as pale yellow crystals.

[0428]¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.0 Hz), 1.71 (2H, m), 1.95 (2H,m), 2.98 (2H, m), 3.30 (2H, m), 3.40-3.60 (4H, m), 3.71 (2H, s), 3.79(2H, s), 4.06 (2H, q, J=7.0 Hz), 4.35 (2H, brs), 4.60 (1H, brs), 5.49(1H, d, J=11.0 Hz), 5.83 (1H, s), 5.92 (1H, d, J=17.6 Hz), 6.16 (1H, d,J=6.4 Hz), 6.77 (1H, dd, J=11.0, 17.6 Hz), 7.58 (2H, d, J=8.4 Hz),7.70-7.80 (3H, m).

EXAMPLE 281-{[1-(2-Dimethylamino-4-pyridyl)-4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-viylbenzensulfonyl)-2-piperazinone

[0429] 4-Chloro-2-(dimethylamino)pyridine hydrochloride (198 mg),triethylamine (700 mg) and ethanol (15 ml) were added to1-{[4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzenesulfonyl)-2-piperazinonehydrochloride (250 mg), to react at 155° C. for 20 hours in a sealedtube. The reaction solution was concentrated, a 10% aqueous sodiumcarbonate solution was added to the residue, the material was extractedwith dichloromethane, dried, and concentrated. The resulting residue wasdried, concentrated, purified by column chromatography(dichloromethane:10% aqueous ammonia-containing methanol=20:1), andcrystallized from ether to obtain the title compound (58 mg) as paleyellow crystals.

[0430]¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=7.0 Hz), 1.73 (2H, m), 1.99 (2H,m), 2.99 (2H, m), 3.05 (6H, s), 3.30 (2H, m), 3.45-3.70 (4H, m), 3.72(2H, s), 3.75 (2H, s), 4.05 (2H, q, J=7.0 Hz), 4.52 (1H, brs), 5.48 (1H,d, J=11.0 Hz), 5.77 (1H, s), 5.92 (1H, d, J=17.6 Hz), 6.10 (1H, d, J=5.8Hz), 6.76 (1H, dd, J=11.0, 17.6 Hz), 7.58 (2H, d, J=8.2 Hz), 7.75 (2H,d, J=8.2 Hz), 7.90 (1H, d, J=5.8 Hz).

EXAMPLE 291-(1-Acetoimidoyl-4-ethoxycarbonylamino-4-piperidylmethyl)-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinoneHydrochloride

[0431] A 4N hydrochloric acid solution in ethyl acetate (30 ml) andethanol (6 ml) were added to1-[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone(5.21 g), and the mixture was stirred at room temperature for 1 hour.The reaction solution was concentrated, the precipitated crystals werefiltered, washed with ethyl acetate-ethanol, and dried to obtain1-[4-ethoxycarbonylamino-4-piperidinylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinonehydrochloride (3.71 g). Ethyl acetimidate hydrochloride(148 mg) andtriethylamine (0.337 ml) were added to a solution of1-[4-ethoxycarbonylamino-4-piperidinylmthyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinonehydrochloride (218 mg) in methanol (10 ml) under ice-cooling, and themixture was stirred at room temperature overnight. After distillation ofthe solvent, purification by CHP20 column chromatography(water:acetonitrile:1N hydrochloric acid=100:0:0→60:40:0.5) afforded thecolorless amorphous title compound (190 mg).

[0432]¹H-NMR (DMSO-d₆) δ: 1.15 (3H, t, J=7.0 Hz), 1.40-1.67 (2H, m),2.00-2.18 (2H, m), 2.22 (3H, s), 2.95-4.00 (12H, m), 3.97 (2H, q, J=7.0Hz), 7.16 (1H, brs), 7.75 (1H, dd, J=8.7, 2.1 Hz), 7.90 (1H, dd, J=8.7,1.7 Hz), 8.21 (1H, d, J=8.8 Hz), 8.26-8.35 (2H, m), 8.61 (1H, s), 8.65(1H, brs), 9.25(1H, brs).

EXAMPLE 304-(4-Bromobenzenesulfonyl)-1-{[4-ethoxycarbonylamino-1-(4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone

[0433] A mixture of benzyl4-[[4-[(ethoxycarbonyl)amino]-1-(4-pyridinyl)-4-piperidinyl]methyl]-3-oxo-1-piperidincarboxylate(450 mg) obtained in Reference Example 9, 4N hydrochloric acid/ethylacetate (0.25 ml), 10% Pd—C (100 mg) and methanol (20 ml) was stirredfor 1 hour under the hydrogen atmosphere. The catalyst was removed byfiltration, and the filtrate was concentrated under reduced pressure.Then, methylene chloride (20 ml) and triethylamine (400 mg) were addedto the resulting residue to dissolve the material,4-bromobenzenesulfonyl chloride (255 mg) was added at 0° C. and themixture was stirred at room temperature for 2 hours. The reactionsolution was washed with 1N sodium hydroxide and water, dried withmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (dichloromethane:10%aqueous ammonia-containing methanol=20:1) to obtain the title compound(364 mg) as colorless crystals.

[0434]¹H-NMR (CDCl₃) δ:1.24 (3H, t, J=7.0 Hz), 1.75 (2H, m), 2.05 (2H,m), 3.05 (2H, m), 3.30 (2H, m), 3.50-3.70 (4H, m), 3.74 (4H, s), 4.07(2H, q, J=7.0 Hz), 4.64 (1H, br s), 6.64 (2H, d, J=6.6 Hz), 7.70-7.98(4H, m), 7.65 (2H, d, J=8.6 Hz), 7.74 (2H, d, J=8.6 Hz), 8.26 (2H, d,J=6.6 Hz). IR (KBr): 1715, 1659, 1597, 1512, 1352, 1260, 1171 cm⁻¹.

EXAMPLE 314-(4-Bromobenzenesulfonyl)-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone

[0435] Triethylamine (400 mg) was added to a solution of1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinonehydrochloride (440 mg) obtained in Reference Example 11 indichloromethane (15 ml), 4-bromobenzenesulfonyl chloride (255 mg) wasadded at 0° C., and the mixture was stirred at room temperature for 1hour. An aqueous sodium carbonate solution was added to the reactionsolution, the material was extracted with dichloromethane, dried,concentrated, and purified by silica gel column chromatography(dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtainthe title compound (403 mg) as colorless crystals.

[0436]¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.0 Hz), 1.75 (2H, m), 2.04 (2H,m), 2.46 (3H, s), 3.06 (2H, m), 3.30 (2H, m), 3.50-3.70 (4H, m), 3.74(4H, s), 4.07 (2H, q, J=7.0 Hz), 4.57 (1H, s), 6.45-6.55 (2H, m), 7.66(2H, d, J=9.0 Hz), 7.74 (1H, dd, J=9.0 Hz), 8.17 (1H, d, J=6.6 Hz). IR(KBr): 1715, 1651, 1601, 1537, 1352, 1260, 1171 cm⁻¹.

FORMULATION EXAMPLE 1

[0437] An FXa inhibitor (e.g., deep vein thrombosis treating agent,cardiogenic cerebral infarction treating agent, and the like) containinga compound represented by the formula (I) according to the presentinvention or a salt thereof as an active ingredient can be produced forexample by the following formulations. 1. Capsule (1) Compound obtainedin Example 2  40 mg (2) Lactose  70 mg (3) Microcrystalline cellulose  9mg (4) Magnesium stearate  1 mg 1 Capsule 120 mg

[0438] Components (1), (2) and (3) and a half of (4) are mixed andgranulated. Then the remainder of Component (4) was added and the entiremass is filled into gelatin capsules. 2. Tablet (1) Compound obtained inExample 2 40 mg (2) Lactose 58 mg (3) Corn starch 18 mg (4)Microcrystalline cellulose 3.5 mg (5) Magnesium stearate 0.5 mg 1 Table120 mg

[0439] Components (1), (2) and (3) and a ⅔ of (4) and a half ofComponent (5) are mixed and granulated. Then the remainders ofComponents (4) and (5) are added to the granule, and then compressedinto tablets.

FORMULATION EXAMPLE 2

[0440] 50 mg of the compound obtained in Example 2 was dissolved in 50ml of JP distilled water for injection, and JP distilled water forinjection was further added to make 100 ml. This solution was filteredaseptically, and 1 ml aliquots of this solution were dispensedaseptically into injection vials, which were lyophilized and closedtightly.

Experiment 1

[0441] (1) Human Activated Coagulation Factor X (FXa) InhibitingActivity

[0442] Method: A cuvette was charged with 225 μl of 0.05 M tris buffer(pH 8.3) containing 0.145 M sodium chloride and 2 mM calcium chloride, 5μl of a sample (test compound dissolved in dimethyl sulfoxide) and 10 μlof human FXa (0.3 unit/ml), which were reacted at 37° C. for 10 minutesand then combined with 10 μl of a substrate (3 mM, S-2765) and furtherreacted at 37° C. for 10 minutes. Then the reaction was terminated byadding 25 μl of 50% aqueous acetic acid, and the change in theabsorbance at 405 nm was determined using a spectrophotometer tocalculate the concentration at which the FXa effect was inhibited by 50%(IC₅₀).

[0443] (2) In vitro Clotting Time Measurement

[0444] (2-1) Prothrombin Time (PT) Measurement:

[0445] A PT-test WAKO (WAKO PURE CHEMICAL) was employed together with anautomatic coagulometer (STA compact DIAGNOSTICA STAGO). 97 μl of Humannormal plasma (fresh human plasma, FFP, SEKISUI KAGAKU KOGYO) wascombined with 3 μl of a test substance and pre-incubated at 37° C. for 4minutes. 50 μl of the plasma described above was combined with 100 μl ofrabbit brain-derived tissue thromboplastin solution and the time for theclotting was measured. The test substance was used after dissolving indimethyl sulfoxide (DMSO). A concentration required for 2-foldprolongation of the clotting time was calculated based on the clottingtime observed when DMSO was added instead of the test substance.

[0446] (2-2) Intrinsic Clotting Time (APTT) Measurement:

[0447] A STA-APTT-LT (DIAGNOSTICA STAGO) was employed with together withan automatic coagulometer (STA compact DIAGNOSTICA STAGO). 97 μl ofhuman normal plasma (fresh human plasma, FFP, SEKISUI KAGAKU KOGYO) wascombined with 3 μl of a test substance. 50 μl of the plasma was combinedwith 50 μl of an active partial thromboplastin solution and preincubatedat 37° C. for 4 minutes. 50 μl of 20 mmol/L CaCl₂ was added and the timefor the clotting was determined. The test substance was used afterdissolving in DMSO. A concentration required for 2-fold prolongation ofthe clotting time was calculated based on the clotting time observedwhen DMSO was added instead of the test substance.

[0448] (2-3) Thrombin Clotting Time (TT) Measurement:

[0449] An automatic coagulometer (Biomatic B10, Sarstedt) was employedfor a measurement. Human plasma-derived thrombin (Sigma) was dissolvedin distilled water at 2.3 NIH unit/ml. 97 μl of human normal plasma(fresh human plasma, FFP, SEKISUI KAGAKU KOGYO) was combined with 3 μlof a test substance and pre-incubated at 37° C. for 3 minutes. 100 μl ofthe plasma described above was combined with 200 μl of a thrombinsolution, and the time for the clotting was measured. The test substancewas used after dissolving in DMSO. A concentration required for 2-foldprolongation of the clotting time was calculated based on the clottingtime observed when DMSO was added instead of the test substance.

[0450] (3) Ex vivo Clotting Time Measurement (Mice)

[0451] (3-1) Intravenous Administration:

[0452] Male ICR mice (25 to 35 g, Slc) were employed. An animal receiveda test substance by a single administration of 5 ml/kg to a tail veinunder anesthesia with pentobarbital (50 mg/kg, i.p.). 5 Minutes afterthe administration, 0.8 ml of the blood was taken from an abdominalaorta with a 1/10 volume of 3.8% sodium citrate (CYTORAL, YAMANOUCHI),and centrifuged at 3000 rpm for 15 minutes to obtain a plasma. 50 μl ofthe plasma described above was combined with 100 μl of rabbitbrain-derived tissue thromboplastin solution and the time for theclotting was measured. The clotting time was measured using a PT-testWAKO (WAKO PURE CHEMICAL) together with an automatic coagulometer (STAcompact DIAGNOSTICA STAGO). The test substance was used after dissolvingin physiological saline, and the physiological saline was given insteadof the test substance in a control group. The activity of the substanceis indicated as a ratio (%) of the clotting time in a treatment groupbased on the clotting time in the control group.

[0453] (3-2) Oral Administration:

[0454] Male ICR mice (25 to 35 g, Slc) were employed. 5 ml/kg of a testsubstance was given by a forcible oral administration to an animal afterfasting for 12 hours or longer. 1 hour after administration, a blood wastaken from an abdominal aorta under anesthesia with pentobarbital (50mg/kg, i.p.). The test substance was used after suspending in 0.5%methyl cellulose, and 0.5% methyl cellulose was given instead of thetest substance in a control group. Otherwise, the procedure similar tothat for the intravenous administration described above was employed.

[0455] (4) In vivo Antithrombotic Effect Measurement

[0456] (4-1) Rat Arteriovenous Shunt Method:

[0457] A method by Umetsu et al (Thromb. Haemostas., 39, 74-73, (1978))was employed. Male SD rats (weighing 250 to 350 g) were used underanesthesia with pentobarbital (50 mg/kg, i.p.) to form an extracorporealcirculation of a polyethylene tube attached with a silk thread betweenthe left jugular vein and the right jugular vein. In order to prevent ablood coagulation, the tube had previously been filled with aphysiological saline containing heparin (50 U/ml). The blood was allowedto circulate for 15 minutes, the thrombus depositing on the silk threadduring which period was weighed wet. A test substance was given orallyor intravenously. When given orally, the test substance was suspended in0.5% methyl cellulose, and given (5 ml/kg) 2 hours before initiation ofthe experiment to an animal while fasting. In a control group, 0.5%methyl cellulose was given instead of the test substance. When givenintravenously, 1 ml/kg was given to a tail vein 5 minutes beforeinitiating the blood circulation. The test substance was used afterdissolving in physiological saline, and the physiological saline wasgiven instead of the test substance in a control group. The activity ofa test substance is indicated as a ratio (%) of the wet weight of thethrombus in a treatment group based on the wet weight in the controlgroup.

[0458] (4-2) Rat Abdominal Vena Cava Partial Stasis Model

[0459] Male Sprague-Dawley rats (250-400 g, NIPPON CLAIR) were employed.An abdominal vena cava thrombus model was established by a modifiedFinkle's method (Thromb, Haemostas., 79, 431-438, 1998). An abdominalvena cava was exposed carefully under anesthesia with pentobarbital (50mg/kg, i.p.), and the abdominal vena cava was tied at the renal veinbifurcation and at 1 cm downstream thereof, between which all brancheswere ligated. A balloon catheter (Fogarty, 2F, Baxter) was inserted fromthe left femoral vein, and the region between the two ties was injuredthree times by means of the balloon inflated with 200 to 300 ml of air.The balloon catheter was removed, the thread tied at the renal veinbifurcation was bound together with a 26G needle, and then the needlewas removed, whereby establishing a partial stasis. After 30 minutes,another thread was bound, and the thrombus formed between the twothreads was isolated carefully, and its wet weight was measured using ahooded analytical balance (BP110S, Sartorius). On the other hand, 2 mlof the blood was taken from an abdominal aorta with a {fraction (1/10)}volume of 3.8% sodium citrate (CYTORAL, YAMANOUCHI), and centrifuged at3000 rpm for 10 minutes to obtain a platelet-poor plasma (PPP). A testsubstance was given orally or intravenously. When given orally, the testsubstance was suspended in 0.5% methyl cellulose, and given (5 ml/kg) 2hours before initiation of the experiment to an animal while fasting. Ina control group, 0.5% methyl cellulose was given instead of the testsubstance. When given intravenously, 1 ml/kg was given to a tail vein 5minutes before initiating the partial stasis. The test substance wasused after dissolving in physiological saline, and the physiologicalsaline was given instead of the test substance in a control group. Theactivity (% inhibition of thrombus formation) of a test substance isindicated as a ratio (%) of the wet weight of the thrombus in atreatment group based on the wet weight in the control group.

[0460] (4-3) Rat Deep Vein Thrombosis (DVT) Model

[0461] Male SD rats (weighing 250 to 350 g) were employed. Apolyethylene tube was inserted into the left femoral vein underanesthesia with pentobarbital (50 mg/kg, i.p.). In the polyethylenetube, a silk thread (5 cm in length) which had previously been attachedto a guide wire was inserted, and a physiological saline containingheparin (50 U/ml) was filled in order to prevent a blood coagulation.After inserting the polyethylene to reach the abdominal vena cava, thesilk thread was placed in the abdominal vena cava using the guide wire.After placing for 30 minutes, heparin (200 U/kg) was given intravenouslyfrom a tail vein. After exsanguinating by cutting a brachial artery, theabdominal region was opened and the silk thread was taken out andexamined for the wet weight of the thrombus depositing on the thread(including the weight of the thread). A test substance was given at 1ml/kg to a tail vein 5 minutes before placing the silk thread. The testsubstance was used after dissolving in physiological saline, and thephysiological saline was given instead of the test substance in acontrol group. The wet weight only of the thrombus was calculated as(wet weight of thrombus depositing on silk thread)−(wet weightdetermined after immersing silk thread in heparinized venous blood(11.6±0.2 mg)).

Experimental Results

[0462] IC₅₀ value of human FXa inhibiting activity and PT 2-foldextending concentration (CT2) are shown in Table 1. From this result, itis evident that the compound of the present invention has an excellentFXa inhibiting activity, and exhibits a strong anti-blood coagulationactivity. TABLE 1 Fxa PT Example No. IC₅₀ (μM) CT2 (μM) 1 0.0046 0.27

Industrial Applicability

[0463] Compound (I) of the present invention or a salt thereof has theexcellent FXa inhibiting activity, has a less hemorrhagic side effect,is useful as an anticoagulant capable of being orally absorbed, and thuscan advantageously be used for preventing and/or treating variousdiseases attributable to thrombus or infarction.

1. A compound represented by the formula:

wherein R¹ denotes a group represented by the formula:

(wherein Y¹ denotes O, NH, S, CH₂CH₂, CH═CH, N═CH, OCH₂, SCH₂ or twohydrogen atoms), or a group represented by the formula:

(wherein Y² denotes O, S, N═C or CH═CH), each of which may besubstituted, ring A denotes a nitrogen-containing heterocyclic ringwhich is substituted with an oxo group and may be further substituted,R² denotes a hydrogen atom, an optionally substituted C₁₋₄ alkyl group,an optionally esterified carboxyl group or a cyano group, R³ denotes aC₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which may besubstituted with a substituent selected from a halogen atom, a hydroxygroup, an optionally substituted alkoxy group, an optionally substitutedamino group and an optionally esterified carboxyl group, and Z denotes(1) an optionally substituted amino group, (2) an optionally substitutedhydrocarbon group, (3) an optionally substituted imidoyl group or (4) anoptionally substituted nitrogen-containing heterocyclic group, or a saltthereof.
 2. The compound according to claim 1, wherein R¹ is anoptionally substituted naphthyl group.
 3. The compound according toclaim 1, wherein R¹ is 6-halogeno-2-naphthyl group.
 4. The compoundaccording to claim 1, wherein R¹ is an optionally substitutedbenzopyranyl group.
 5. The compound according to claim 1, wherein R¹ is7-halogeno-2H-3-benzopyranyl group.
 6. The compound according to claim1, wherein R¹ is an optionally substituted phenyl group.
 7. The compoundaccording to claim 1, wherein R¹ is 4-C₂₋₄ alkenyl-phenyl group.
 8. Thecompound according to claim 1, wherein ring A is a ring represented by:

wherein n denotes 1 or 2, and m denotes 2 or
 3. 9. The compoundaccording to claim 1, wherein ring A is an optionally substitutedoxopiperazine ring.
 10. The compound according to claim 1, wherein R² isa hydrogen atom.
 11. The compound according to claim 1, wherein R³ is aC₁₋₄ alkyl group which may be substituted with a substituent selectedfrom a halogen atom, a hydroxy group, an optionally substituted alkoxygroup, an optionally substituted amino group and an optionallyesterified carboxyl group.
 12. The compound according to claim 1,wherein R³ is methyl, ethyl, or propyl.
 13. The compound according toclaim 1, wherein Z is an optionally substituted imidoyl group.
 14. Thecompound according to claim 1, wherein Z is an optionally substitutedC₁₋₄ imidoyl group.
 15. The compound according to claim 1, wherein Z isan optionally substituted amidino group.
 16. The compound according toclaim 1, wherein Z is an optionally substituted nitrogen-containingheterocyclic group.
 17. The compound according to claim 1, wherein Z isa nitrogen-containing heterocyclic group which may be substituted with asubstituent selected from a C₁₋₄ alkyl group and an optionallysubstituted amino group.
 18. The compound according to claim 1, whereinZ is an optionally substituted pyrimidyl group.
 19. The compoundaccording to claim 1, wherein Z is an optionally substituted pyridylgroup.
 20. The compound according to claim 1, which is a compoundselected form the group consisting of4-(6-chloronaphthalene-2-sulfonyl)-1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,4-(6-chloronaphthalene-2-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone,1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-propoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone,1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-bromobenzenesulfonyl)-2-piperazinoneand1-[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)piperidin-4-ylmethyl]-4-(4-bromobenzenesulfonyl)-2-piperazinoneor a salt thereof.
 21. A prodrug of a compound represented by theformula:

wherein R¹ denotes a group represented by the formula:

(wherein Y¹ denotes O, NH, S, CH₂CH₂, CH═CH, N═CH, OCH₂, SCH₂ or twohydrogen atoms), or a group represented by the formula:

(wherein Y² denotes O, S, N═C or CH═CH), each of which may besubstituted, ring A denotes a nitrogen-containing heterocyclic ringwhich is substituted with an oxo group and may be further substituted,R² denotes a hydrogen atom, an optionally substituted C₁₋₄ alkyl group,an optionally esterified carboxyl group or a cyano group, R³ denotes aC₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which may besubstituted with a substituent selected from a halogen atom, a hydroxygroup, an optionally substituted alkoxy group, an optionally substitutedamino group and an optionally esterified carboxyl group, and Z denotes(1) an optionally substituted amino group, (2) an optionally substitutedhydrocarbon group, (3) an optionally substituted imidoyl group or (4) anoptionally substituted nitrogen-containing heterocyclic group, or a saltthereof.
 22. A pharmaceutical composition, which comprises a compoundrepresented by the formula:

wherein R¹ denotes a group represented by the formula:

(wherein Y¹ denotes O, NH, S, CH₂CH₂, CH═CH, N═CH, OCH₂, SCH₂ or twohydrogen atoms), or a group represented by the formula:

(wherein Y² denotes O, S, N═C or CH═CH), each of which may besubstituted, ring A denotes a nitrogen-containing heterocyclic ringwhich is substituted with an oxo group and may be further substituted,R² denotes a hydrogen atom, an optionally substituted C₁₋₄ alkyl group,an optionally esterified carboxyl group or a cyano group, R³ denotes aC₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which may besubstituted with a substituent selected from a halogen atom, a hydroxygroup, an optionally substituted alkoxy group, an optionally substitutedamino group and an optionally esterified carboxyl group, and Z denotes(1) an optionally substituted amino group, (2) an optionally substitutedhydrocarbon group, (3) an optionally substituted imidoyl group or (4) anoptionally substituted nitrogen-containing heterocyclic group, or a saltthereof, or a prodrug thereof.
 23. The composition according to claim22, which is an anticoagulant.
 24. The composition according to claim22, which is an activated blood coagulation factor X inhibiting agent.25. The composition according to claim 22, which is an agent forpreventing and/or treating cardiac infarction, cerebral thrombosis, deepvein thrombosis, pulmonary thrombotic embolus or thrombotic embolusduring or after operation.
 26. A process for preparing a compoundrepresented by the formula:

wherein each symbol is as defined hereinafter, or a salt thereof, whichcomprises (1) reacting a compound represented by the formula: R¹SO₂Qwherein Q denotes a leaving group, and the other symbol is as defined inclaim 1, or a salt thereof, with a compound represented by the formula:

wherein the symbols are as defined in claim 1, or a salt thereof, (2)reacting a compound represented by the formula:

wherein symbols are as defined in claim 1, or a salt thereof, with acompound represented by the formula: L¹-Z wherein L¹ denotes a leavinggroup, and the other symbol is as defined in claim 1, or a salt thereof,or (3) reacting a compound represented by the formula;

wherein the symbols are as defined in claim 1, or a salt thereof, with acompound represented by the formula: L²-COOR³ wherein L² denotes aleaving group, and the other symbol is as defined in claim 1, or a saltthereof.
 27. A method for inhibiting blood coagulation in a mammal,which comprises administering an effective amount of the compoundaccording to claim 1 or a salt thereof, or a prodrug thereof to themammal.
 28. A method for inhibiting activated blood coagulation factor Xin a mammal, which comprises administering an effective amount of thecompound according to claim 1 or a salt thereof, or a prodrug thereof tothe mammal.
 29. A method for preventing and/or treating cardiacinfarction, cerebral thrombosis, deep vein thrombosis, pulmonarythrombotic embolus or thrombotic embolus during or after operation in amammal, which comprises administering an effective amount of thecompound according to claim 1 or a salt thereof, or a prodrug thereof tothe mammal.
 30. Use of the compound according to claim 1 or a saltthereof, or a prodrug thereof for manufacturing a medicament forinhibiting blood coagulation.
 31. Use of the compound according to claim1 or a salt thereof, or a prodrug thereof for manufacturing a medicamentfor inhibiting activated blood coagulation factor X.
 32. Use of thecompound according to claim 1 or a salt thereof, or a prodrug thereoffor manufacturing a medicament for preventing and/or treating cardiacinfarction, cerebral thrombosis, deep vein thrombosis, pulmonarythrombotic embolus or thrombotic embolus during or after operation.